Pyrazole derivatives as protein kinase modulators

ABSTRACT

The invention provides compounds of the formula (I) having protein kinase B inhibiting activity: 
                         
wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R 1  and NR 2 R 3  and a maximum chain length of 4 atoms extending between E and NR 2 R 3 , wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the NR 2 R 3  group and provided that the oxo group when present is located at a carbon atom α with respect to the NR 2 R 3  group;
     E is a monocyclic or bicyclic carbocyclic or heterocyclic group;   R 1  is an aryl or heteroaryl group; and   R 2 , R 3 , R 4  and R 5  are as defined in the claims.   

     Also provided are pharmaceutical compositions containing the compounds, methods for preparing the compounds and their use as anticancer agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/536,174 (which published as U.S. 2013-0005702 A1 on Jan. 3, 2013)filed Jun. 28, 2012, which is a continuation of U.S. application Ser.No. 10/596,788 (which published as U.S. 2011-0144080 A1 on Jun. 16,2011, and issued as U.S. Pat. No. 8,247,576 on Aug. 21, 2012), which isa national phase filing under 35 U.S.C. §371 of PCT InternationalApplication PCT/GB2004/005464, filed Dec. 23, 2004, and published underPCT Article 21(2) in English as WO 2005/061463 on Jul. 7, 2005, whichclaimed priority to British application 03 29617.5, filed Dec. 23, 2003,and to United States Provisional Application Nos. 60/532,199, filed Dec.23, 2003 and 60/577,843, filed Jun. 8, 2004. The entire contents of eachof the prior applications are incorporated herein by reference.

This invention relates to pyrazole-containing aryl- andheteroaryl-alkylamine compounds that inhibit or modulate the activity ofprotein kinase B (PKB) and protein kinase A (PKA), to the use of thecompounds in the treatment or prophylaxis of disease states orconditions mediated by PKB and PKA, and to novel compounds having PKBand PKA inhibitory or modulating activity. Also provided arepharmaceutical compositions containing the compounds and novel chemicalintermediates.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).

Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

Apoptosis or programmed cell death is an important physiological processwhich removes cells no longer required by an organism. The process isimportant in early embryonic growth and development allowing thenon-necrotic controlled breakdown, removal and recovery of cellularcomponents. The removal of cells by apoptosis is also important in themaintenance of chromosomal and genomic integrity of growing cellpopulations. There are several known checkpoints in the cell growthcycle at which DNA damage and genomic integrity are carefully monitored.The response to the detection of anomalies at such checkpoints is toarrest the growth of such cells and initiate repair processes. If thedamage or anomalies cannot be repaired then apoptosis is initiated bythe damaged cell in order to prevent the propagation of faults anderrors. Cancerous cells consistently contain numerous mutations, errorsor rearrangements in their chromosomal DNA. It is widely believed thatthis occurs in part because the majority of tumours have a defect in oneor more of the processes responsible for initiation of the apoptoticprocess. Normal control mechanisms cannot kill the cancerous cells andthe chromosomal or DNA coding errors continue to be propagated. As aconsequence restoring these pro-apoptotic signals or suppressingunregulated survival signals is an attractive means of treating cancer.

The signal transduction pathway containing the enzymesphosphatidylinositol 3-kinase (PI3K), PDK1 and PKB amongst others, haslong been known to mediate increased resistance to apoptosis or survivalresponses in many cells. There is a substantial amount of data toindicate that this pathway is an important survival pathway used by manygrowth factors to suppress apoptosis. The enzyme PI3K is activated by arange of growth and survival factors e.g. EGF, PDGF and through thegeneration of polyphosphatidylinositols, initiates the activation of thedownstream signalling events including the activity of the kinases PDK1and protein kinase B (PKB) also known as Akt. This is also true in hosttissues, e.g. vascular endothelial cells as well as neoplasias. PKB is aprotein ser/thr kinase consisting of a kinase domain together with anN-terminal PH domain and C-terminal regulatory domain. The enzyme PKBitself is phosphorylated on Thr 308 by PDK1 and on Ser 473 by an as yetunidentified kinase. Full activation requires phosphorylation at bothsites whilst association between PIP3 and the PH domain is required foranchoring of the enzyme to the cytoplasmic face of the lipid membraneproviding optimal access to substrates.

Activated PKB in turn phosphorylates a range of substrates contributingto the overall survival response. Whilst we cannot be certain that weunderstand all of the factors responsible for mediating the PKBdependent survival response, some important actions are believed to bephosphorylation and inactivation of the pro-apoptotic factor BAD andcaspase 9, phosphorylation of Forkhead transcription factors e.g. FKHRleading to their exclusion from the nucleus, and activation of theNfkappaB pathway by phosphorylation of upstream kinases in the cascade.

In addition to the anti-apoptotic and pro-survival actions of the PKBpathway, the enzyme also plays an important role in promoting cellproliferation. This action is again likely to be mediated via severalactions, some of which are thought to be phosphorylation andinactivation of the cyclin dependent kinase inhibitor ofp21^(Cip1/WAF1), and phosphorylation and activation of mTOR, a kinasecontrolling several aspects of cell growth.

The phosphatase PTEN which dephosphorylates and inactivatespolyphosphatidylinositols is a key tumour suppressor protein whichnormally acts to regulate the PI3K/PKB survival pathway. Thesignificance of the PI3K/PKB pathway in tumourigenesis can be judgedfrom the observation that PTEN is one of the most common targets ofmutation in human tumours, with mutations in this phosphatase havingbeen found in ˜50% or more of melanomas (Guldberg et al 1997, CancerResearch 57, 3660-3663) and advanced prostate cancers (Cairns et al 1997Cancer Research 57, 4997). These observations and others suggest that awide range of tumour types are dependent on the enhanced PKB activityfor growth and survival and would respond therapeutically to appropriateinhibitors of PKB.

There are 3 closely related isoforms of PKB called alpha, beta andgamma, which genetic studies suggest have distinct but overlappingfunctions. Evidence suggests that they can all independently play a rolein cancer. For example PKB beta has been found to be over-expressed oractivated in 10-40% of ovarian and pancreatic cancers (Bellacosa et al1995, Int. J. Cancer 64, 280-285; Cheng et al 1996, PNAS 93, 3636-3641;Yuan et al 2000, Oncogene 19, 2324-2330), PKB alpha is amplified inhuman gastric, prostate and breast cancer (Staal 1987, PNAS 84,5034-5037; Sun et al 2001, Am. J. Pathol. 159, 431-437) and increasedPKB gamma activity has been observed in steroid independent breast andprostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274,21528-21532).

The PKB pathway also functions in the growth and survival of normaltissues and may be regulated during normal physiology to control celland tissue function. Thus disorders associated with undesirableproliferation and survival of normal cells and tissues may also benefittherapeutically from treatment with a PKB inhibitor. Examples of suchdisorders are disorders of immune cells associated with prolongedexpansion and survival of cell population leading to a prolonged or upregulated immune response. For example, T and B lymphocyte response tocognate antigens or growth factors such as interleukin-2 activates thePI3K/PKB pathway and is responsible for maintaining the survival of theantigen specific lymphocyte clones during the immune response. Underconditions in which lymphocytes and other immune cells are responding toinappropriate self or foreign antigens, or in which other abnormalitieslead to prolonged activation, the PKB pathway contributes an importantsurvival signal preventing the normal mechanisms by which the immuneresponse is terminated via apoptosis of the activated cell population.There is a considerable amount of evidence demonstrating the expansionof lymphocyte populations responding to self antigens in autoimmuneconditions such as multiple sclerosis and arthritis. Expansion oflymphocyte populations responding inappropriately to foreign antigens isa feature of another set of conditions such as allergic responses andasthma. In summary inhibition of PKB could provide a beneficialtreatment for immune disorders.

Other examples of inappropriate expansion, growth, proliferation,hyperplasia and survival of normal cells in which PKB may play a roleinclude but are not limited to atherosclerosis, cardiac myopathy andglomerulonephritis.

In addition to the role in cell growth and survival, the PKB pathwayfunctions in the control of glucose metabolism by insulin. Availableevidence from mice deficient in the alpha and beta isoforms of PKBsuggests that this action is mediated by the beta isoform. As aconsequence, modulators of PKB activity may also find utility indiseases in which there is a dysfunction of glucose metabolism andenergy storage such as diabetes, metabolic disease and obesity.

Cyclic AMP-dependent protein kinase (PKA) is a serine/threonine proteinkinase that phosphorylates a wide range of substrates and is involved inthe regulation of many cellular processes including cell growth, celldifferentiation, ion-channel conductivity, gene transcription andsynaptic release of neurotransmitters. In its inactive form, the PKAholoenzyme is a tetramer comprising two regulatory subunits and twocatalytic subunits.

PKA acts as a link between G-protein mediated signal transduction eventsand the cellular processes that they regulate. Binding of a hormoneligand such as glucagon to a transmembrane receptor activates areceptor-coupled G-protein (GTP-binding and hydrolyzing protein). Uponactivation, the alpha subunit of the G protein dissociates and binds toand activates adenylate cyclase, which in turn converts ATP tocyclic-AMP (cAMP). The cAMP thus produced then binds to the regulatorysubunits of PKA leading to dissociation of the associated catalyticsubunits. The catalytic subunits of PKA, which are inactive whenassociated with the regulatory sub-units, become active upondissociation and take part in the phosphorylation of other regulatoryproteins.

For example, the catalytic sub-unit of PKA phosphorylates the kinasePhosphorylase Kinase which is involved in the phosphorylation ofPhosphorylase, the enzyme responsible for breaking down glycogen torelease glucose. PKA is also involved in the regulation of glucoselevels by phosphorylating and deactivating glycogen synthase. Thus,modulators of PKA activity (which modulators may increase or decreasePKA activity) may be useful in the treatment or management of diseasesin which there is a dysfunction of glucose metabolism and energy storagesuch as diabetes, metabolic disease and obesity.

PKA has also been established as an acute inhibitor of T cellactivation. Anndahl et al, have investigated the possible role of PKAtype I in HIV-induced T cell dysfunction on the basis that T cells fromHIV-infected patients have increased levels of cAMP and are moresensitive to inhibition by cAMP analogues than are normal T cells. Fromtheir studies, they concluded that increased activation of PKA type Imay contribute to progressive T cell dysfunction in HIV infection andthat PKA type I may therefore be a potential target for immunomodulatingtherapy. Aandahl, E. M., Aukrust, P., Skålhegg, B. S., Müller, F.,Frøland, S. S., Hansson, V., Taskén, K. Protein kinase A type Iantagonist restores immune responses of T cells from HIV-infectedpatients. FASEB J. 12, 855-862 (1998).

It has also been recognised that mutations in the regulatory sub-unit ofPKA can lead to hyperactivation in endocrine tissue.

Because of the diversity and importance of PKA as a messenger in cellregulation, abnormal responses of cAMP can lead to a variety of humandiseases such as irregular cell growth and proliferation (Stratakis, C.A.; Cho-Chung, Y. S., Protein Kinase A and human diseases. TrendsEndrocri. Metab. 2002, 13, 50-52). Over-expression of PKA has beenobserved in a variety of human cancer cells including those fromovarian, breast and colon patients. Inhibition of PKA would therefore bean approach to treatment of cancer (Li, Q.; Zhu, G-D.; Current Topics inMedicinal Chemistry, 2002, 2, 939-971).

For a review of the role of PKA in human disease, see for example,Protein Kinase A and Human Disease, Edited by Constantine A. Stratakis,Annals of the New York Academy of Sciences, Volume 968, 2002, ISBN1-57331-412-9.

Several classes of compounds have been disclosed as having PKA and PKBinhibitory activity.

For example, a class of isoquinolinyl-sulphonamido-diamines having PKBinhibitory activity is disclosed in WO 01/91754 (Yissum).

WOO/07996 (Chiron) discloses substituted pyrazoles having estrogenreceptor agonist activity. The compounds are described as being usefulin treating or preventing inter alia estrogen-receptor mediated breastcancer. PKB inhibitory activity is not disclosed.

WO 00/31063 (Searle) discloses substituted pyrazole compounds as p38kinase inhibitors.

WO 01/32653 (Cephalon) discloses a class of pyrazolone kinaseinhibitors. WO 03/059884 (X-Ceptor Therapeutics) discloses N-substitutedpyridine compounds as modulators of nuclear receptors.

WO 03/068230 (Pharmacia) discloses substituted pyridones as p38 MAPkinase modulators.

WO 00/66562 (Dr Reddy's Research Foundation) discloses a class of1-phenyl-substituted pyrazoles for use as anti-inflammatory agents. The1-phenyl group is substituted by a sulphur-containing substituent as asulphonamide or sulphonyl group.

SUMMARY OF THE INVENTION

The invention provides compounds that have protein kinase B (PKB) andprotein A (PKA) inhibiting or modulating activity, and which it isenvisaged will be useful in preventing or treating disease states orconditions mediated by PKB or PKA.

In a first aspect, the invention provides a compound of the formula (I):

or a salt, solvate, tautomer or N-oxide thereof;wherein A is a saturated hydrocarbon linker group containing from 1 to 7carbon atoms, the linker group having a maximum chain length of 5 atomsextending between R¹ and NR²R³ and a maximum chain length of 4 atomsextending between E and NR²R³, wherein one of the carbon atoms in thelinker group may optionally be replaced by an oxygen or nitrogen atom;and wherein the carbon atoms of the linker group A may optionally bearone or more substituents selected from oxo, fluorine and hydroxy,provided that the hydroxy group when present is not located at a carbonatom α with respect to the NR²R³ group and provided that the oxo groupwhen present is located at a carbon atom α with respect to the NR²R³group;

E is a monocyclic or bicyclic carbocyclic or heterocyclic group;

R¹ is an aryl or heteroaryl group;

R² and R³ are independently selected from hydrogen, C₁₋₄ hydrocarbyl andC₁₋₄ acyl wherein the hydrocarbyl and acyl moieties are optionallysubstituted by one or more substituents selected from fluorine, hydroxy,amino, methylamino, dimethylamino and methoxy;

or R² and R³ together with the nitrogen atom to which they are attachedform a cyclic group selected from an imidazole group and a saturatedmonocyclic heterocyclic group having 4-7 ring members and optionallycontaining a second heteroatom ring member selected from O and N;

or one of R² and R³ together with the nitrogen atom to which they areattached and one or more atoms from the linker group A form a saturatedmonocyclic heterocyclic group having 4-7 ring members and optionallycontaining a second heteroatom ring member selected from O and N;

or NR²R³ and the carbon atom of linker group A to which it is attachedtogether form a cyano group;

R⁴ is selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, C₁₋₅saturated hydrocarbyloxy, cyano, and CF₃; and

R⁵ is selected from selected from hydrogen, halogen, C₁₋₅ saturatedhydrocarbyl, C₁₋₅ saturated hydrocarbyloxy, cyano, CONH₂, CONHR⁹, CF₃,NH₂, NHCOR⁹ or NHCONHR⁹;

R⁹ is a group R^(9a) or (CH₂)R^(9a), wherein R^(9a) is a monocyclic orbicyclic group which may be carbocyclic or heterocyclic;

the carbocyclic group or heterocyclic group R^(9a) being optionallysubstituted by one or more substituents selected from halogen, hydroxy,trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄hydrocarbylamino; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO,X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂;and R^(b) is selected from hydrogen, heterocyclic groups having from 3to 12 ring members, and a C₁₋₈ hydrocarbyl group optionally substitutedby one or more substituents selected from hydroxy, oxo, halogen, cyano,nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclicand heterocyclic groups having from 3 to 12 ring members and wherein oneor more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally bereplaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;

R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and

X¹ is O, S or NR and X² is ═O, ═S or ═NR^(c).

The invention also provides a compound of the formula (Ia):

or a salt, solvate, tautomer or N-oxide thereof;wherein A is a saturated hydrocarbon linker group containing from 1 to 7carbon atoms, the linker group having a maximum chain length of 5 atomsextending between R¹ and NR²R³ and a maximum chain length of 4 atomsextending between E and NR²R³, wherein one of the carbon atoms in thelinker group may optionally be replaced by an oxygen or nitrogen atom;and wherein the carbon atoms of the linker group A may optionally bearone or more substituents selected from oxo, fluorine and hydroxy,provided that the hydroxy group when present is not located at a carbonatom α with respect to the NR²R³ group and provided that the oxo groupwhen present is located at a carbon atom α with respect to the NR²R³group;

E is a monocyclic or bicyclic carbocyclic or heterocyclic group;

R¹ is an aryl or heteroaryl group;

R² and R³ are independently selected from hydrogen, C₁₋₄ hydrocarbyl andC₁₋₄ acyl;

or R² and R³ together with the nitrogen atom to which they are attachedform a saturated monocyclic heterocyclic group having 4-7 ring membersand optionally containing a second heteroatom ring member selected fromO and N;

or one of R² and R³ together with the nitrogen atom to which they areattached and one or more atoms from the linker group A form a saturatedmonocyclic heterocyclic group having 4-7 ring members and optionallycontaining a second heteroatom ring member selected from O and N;

or NR²R³ and the carbon atom of linker group A to which it is attachedtogether form a cyano group;

R⁴ is selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyanoand CF₃; and

R⁵ is selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl,cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹;

R⁹ is phenyl or benzyl each optionally substituted by one or moresubstituents selected from halogen, hydroxy, trifluoromethyl, cyano,nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino; a groupR^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹,S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected fromhydrogen, heterocyclic groups having from 3 to 12 ring members, and aC₁₋₈ hydrocarbyl group optionally substituted by one or moresubstituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy,amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclicgroups having from 3 to 12 ring members and wherein one or more carbonatoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S,SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;

R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and

X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

Also provided are compounds of the general formula (Ib):

or salts, solvates, tautomers or N-oxides thereof;wherein A is a saturated hydrocarbon linker group containing from 1 to 7carbon atoms, the linker group having a maximum chain length of 5 atomsextending between R¹ and NR²R³ and a maximum chain length of 4 atomsextending between E and NR²R³, wherein one of the carbon atoms in thelinker group may optionally be replaced by an oxygen or nitrogen atom,and wherein the carbon atoms of the linker group A may optionally bearone or more substituents selected from fluorine and hydroxy, providedthat the hydroxy group is not located at a carbon atom α with respect tothe NR²R³ group;

E is a monocyclic or bicyclic carbocyclic or heterocyclic group;

R¹ is an aryl or heteroaryl group;

R² and R³ are independently selected from hydrogen, C₁₋₄ hydrocarbyl andC₁₋₄ acyl;

or R² and R³ together with the nitrogen atom to which they are attachedform a saturated monocyclic heterocyclic group having 4-7 ring membersand optionally containing a second heteroatom ring member selected fromO and N;

or one of R² and R³ together with the nitrogen atom to which they areattached and one or more atoms from the linker group A form a saturatedmonocyclic heterocyclic group having 4-7 ring members and optionallycontaining a second heteroatom ring member selected from O and N;

or NR²R³ and the carbon atom of linker group A to which it is attachedtogether form a cyano group;

R⁴ is selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl,cyano, and CF₃; and

R⁵ is selected from selected from hydrogen, halogen, C₁₋₅ saturatedhydrocarbyl, cyano, CONH₂, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹;

R⁹ is phenyl or benzyl each optionally substituted by one orsubstituents selected from halogen, hydroxy, trifluoromethyl, cyano,nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino; a groupR^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹,S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected fromhydrogen, heterocyclic groups having from 3 to 12 ring members, and aC₁₋₈ hydrocarbyl group optionally substituted by one or moresubstituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy,amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclicgroups having from 3 to 12 ring members and wherein one or more carbonatoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S,SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;

R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and

X¹ is O, S or NR and X² is ═O, ═S or ═NR^(c).

The invention further provides:

-   -   A compound per se of the formula (II), (III), (IV), (V) or any        other sub-group or embodiment of the formula (I) as defined        herein.    -   A compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein for use in        the prophylaxis or treatment of a disease state or condition        mediated by protein kinase B.    -   The use of a compound of formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein for the        manufacture of a medicament for the prophylaxis or treatment of        a disease state or condition mediated by protein kinase B.    -   A method for the prophylaxis or treatment of a disease state or        condition mediated by protein kinase B, which method comprises        administering to a subject in need thereof a compound of the        formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any sub-group        thereof as defined herein.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth or abnormally arrested cell        death in a mammal, the method comprising administering to the        mammal a compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein in an        amount effective to inhibit protein kinase B activity.    -   A method of inhibiting protein kinase B, which method comprises        contacting the kinase with a kinase-inhibiting compound of the        formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any sub-group        thereof as defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a protein kinase B using        a compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein.    -   A compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group or embodiment thereof as defined        herein for use in the prophylaxis or treatment of a disease        state or condition mediated by protein kinase A.    -   The use of a compound of formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group or embodiment thereof as defined        herein for the manufacture of a medicament for the prophylaxis        or treatment of a disease state or condition mediated by protein        kinase A.    -   A method for the prophylaxis or treatment of a disease state or        condition mediated by protein kinase A, which method comprises        administering to a subject in need thereof a compound of the        formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any sub-group        or embodiment thereof as defined herein.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth or abnormally arrested cell        death in a mammal, the method comprising administering to the        mammal a compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group or embodiment thereof as defined        herein in an amount effective to inhibit protein kinase A        activity.    -   A method of inhibiting protein kinase A, which method comprises        contacting the kinase with a kinase-inhibiting compound of the        formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any sub-group        or embodiment thereof as defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a protein kinase A using        a compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group or embodiment thereof as defined        herein.    -   The use of a compound of the formula (I), (Ia), (Ib), (II),        (III), (IV), (V) or any sub-group thereof as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of a disease state or condition arising from abnormal cell        growth or abnormally arrested cell death.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth in a mammal, which method        comprises administering to the mammal a compound of the formula        (I), (Ia), (Ib), (II), (III), (IV), (V) or any sub-group thereof        as defined herein in an amount effective in inhibiting abnormal        cell growth or abnormally arrested cell death.    -   A method for alleviating or reducing the incidence of a disease        or condition comprising or arising from abnormal cell growth or        abnormally arrested cell death in a mammal, which method        comprises administering to the mammal a compound of the formula        (I), (Ia), (Ib), (II), (III), (IV), (V) or any sub-group thereof        as defined herein in an amount effective in inhibiting abnormal        cell growth.    -   A pharmaceutical composition comprising a novel compound of the        formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any sub-group        thereof as defined herein and a pharmaceutically acceptable        carrier.    -   A compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein for use in        medicine.    -   The use of a compound of the formula (I), (Ia), (Ib), (II),        (III), (IV), (V) or any sub-group thereof as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of any one of the disease states or conditions disclosed herein.    -   A method for the treatment or prophylaxis of any one of the        disease states or conditions disclosed herein, which method        comprises administering to a patient (e.g. a patient in need        thereof) a compound (e.g. a therapeutically effective amount) of        the formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any        sub-group thereof as defined herein.    -   A method for alleviating or reducing the incidence of a disease        state or condition disclosed herein, which method comprises        administering to a patient (e.g. a patient in need thereof) a        compound (e.g. a therapeutically effective amount) of the        formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any sub-group        thereof as defined herein.    -   A method for the diagnosis and treatment of a disease state or        condition mediated by protein kinase B, which method        comprises (i) screening a patient to determine whether a disease        or condition from which the patient is or may be suffering is        one which would be susceptible to treatment with a compound        having activity against protein kinase B; and (ii) where it is        indicated that the disease or condition from which the patient        is thus susceptible, thereafter administering to the patient a        compound of the formula (I), (Ia), (Ib), (II), (III), (IV), (V)        or any sub-group thereof as defined herein.    -   The use of a compound of the formula (I), (Ia), (Ib), (II),        (III), (IV), (V) or any sub-group thereof as defined herein for        the manufacture of a medicament for the treatment or prophylaxis        of a disease state or condition in a patient who has been        screened and has been determined as suffering from, or being at        risk of suffering from, a disease or condition which would be        susceptible to treatment with a compound having activity against        protein kinase B.    -   A method for the diagnosis and treatment of a disease state or        condition mediated by protein kinase A, which method        comprises (i) screening a patient to determine whether a disease        or condition from which the patient is or may be suffering is        one which would be susceptible to treatment with a compound        having activity against protein kinase A; and (ii) where it is        indicated that the disease or condition from which the patient        is thus susceptible, thereafter administering to the patient a        compound of the formula (I), (Ia), (Ib), (II), (III), (IV), (V)        or any sub-group or embodiment thereof as defined herein.    -   The use of a compound of the formula (I), (Ia), (Ib), (II),        (III), (IV), (V) or any sub-group or embodiment thereof as        defined herein for the manufacture of a medicament for the        treatment or prophylaxis of a disease state or condition in a        patient who has been screened and has been determined as        suffering from, or being at risk of suffering from, a disease or        condition which would be susceptible to treatment with a        compound having activity against protein kinase A.

GENERAL PREFERENCES AND DEFINITIONS

The following general preferences and definitions shall apply to each ofthe moieties A, E and R¹ to R⁵ and R⁹ and any sub-definition, sub-groupor embodiment thereof, unless the context indicates otherwise.

Any references to Formula (I) herein shall be taken also to refer toformulae (Ia), (Ib), (II), (III), (IV), (V) and any other sub-group ofcompounds within formula (I) unless the context requires otherwise.

References to “carbocyclic” and “heterocyclic” groups as used hereinshall, unless the context indicates otherwise, include both aromatic andnon-aromatic ring systems. In general, such groups may be monocyclic orbicyclic and may contain, for example, 3 to 12 ring members, moreusually 5 to 10 ring members. Examples of monocyclic groups are groupscontaining 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7, andpreferably 5 or 6 ring members. Examples of bicyclic groups are thosecontaining 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10ring members.

The carbocyclic or heterocyclic groups can be aryl or heteroaryl groupshaving from 5 to 12 ring members, more usually from 5 to 10 ringmembers. The term “aryl” as used herein refers to a carbocyclic grouphaving aromatic character and the term “heteroaryl” is used herein todenote a heterocyclic group having aromatic character. The terms “aryl”and “heteroaryl” embrace polycyclic (e.g. bicyclic) ring systems whereinone or more rings are non-aromatic, provided that at least one ring isaromatic. In such polycyclic systems, the group may be attached by thearomatic ring, or by a non-aromatic ring. The aryl or heteroaryl groupscan be monocyclic or bicyclic groups and can be unsubstituted orsubstituted with one or more substituents, for example one or moregroups R¹⁰ as defined herein.

The term non-aromatic group embraces unsaturated ring systems withoutaromatic character, partially saturated and fully saturated carbocyclicand heterocyclic ring systems. The terms “unsaturated” and “partiallysaturated” refer to rings wherein the ring structure(s) contains atomssharing more than one valence bond i.e. the ring contains at least onemultiple bond e.g. a C═C, C═C or N═C bond. The term “fully saturated”refers to rings where there are no multiple bonds between ring atoms.Saturated carbocyclic groups include cycloalkyl groups as defined below.Partially saturated carbocyclic groups include cycloalkenyl groups asdefined below, for example cyclopentenyl, cycloheptenyl andcyclooctenyl.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a fivemembered or six membered monocyclic ring or a bicyclic structure formedfrom fused five and six membered rings or two fused six membered rings.Each ring may contain up to about four heteroatoms typically selectedfrom nitrogen, sulphur and oxygen. Typically the heteroaryl ring willcontain up to 3 heteroatoms, more usually up to 2, for example a singleheteroatom. In one embodiment, the heteroaryl ring contains at least onering nitrogen atom. The nitrogen atoms in the heteroaryl rings can bebasic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present m the heteroaryl group,including any amino group substituents of the ring, will be less thanfive.

Examples of five membered heteroaryl groups include but are not limitedto pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole andtetrazole groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring hetero atoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   f) an imidazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   g) an oxazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   h) an isoxazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   i) a thiazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   j) an isothiazole ring fused to a 5- or 6-membered ring        containing 1 or 2 ring heteroatoms;    -   k) a thiophene ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring hetero atoms;    -   l) a furan ring fused to a 5- or 6-membered ring containing 1, 2        or 3 ring hetero atoms;    -   m) an oxazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring hetero atoms;    -   n) an isoxazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring hetero atoms;    -   o) a cyclohexyl ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms; and    -   p) a cyclopentyl ring fused to a 5- or 6-membered ring        containing 1, 2 or 3 ring heteroatoms.

Examples of bicyclic heteroaryl groups containing a six membered ringfused to a five membered ring include but are not limited to benzfuran,benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole,benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline,isoindoline, purine (e.g., adenine, guanine), indazole, benzodioxole andpyrazolopyridine groups.

Examples of bicyclic heteroaryl groups containing two fused six memberedrings include but are not limited to quinoline, isoquinoline, chroman,thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan,quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline,quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

Examples of polycyclic aryl and heteroaryl groups containing an aromaticring and a non-aromatic ring include tetrahydronaphthalene,tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiene,dihydrobenzfuran, 2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, indoline and indane groups.

Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl,and tetrahydronaphthyl groups.

Examples of non-aromatic heterocyclic groups are groups having from 3 to12 ring members, more usually 5 to 10 ring members. Such groups can bemonocyclic or bicyclic, for example, and typically have from 1 to 5heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ringmembers), usually selected from nitrogen, oxygen and sulphur.

The heterocylic groups can contain, for example, cyclic ether moieties(e.g as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g.as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. asin pyrrolidine), cyclic sulphones (e.g. as in sulfolane and sulfolene),cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g.thiomorpholine). Other examples of non-aromatic heterocyclic groupsinclude cyclic amide moieties (e.g. as in pyrrolidone) and cyclic estermoieties (e.g. as in butyrolactone).

Examples of monocyclic non-aromatic heterocyclic groups include 5-, 6-and 7-membered monocyclic heterocyclic groups. Particular examplesinclude morpholine, thiomorpholine and its S-oxide and S,S-dioxide(particularly thiomorpholine), piperidine (e.g. 1-piperidinyl,2-piperidinyl 3-piperidinyl and 4-piperidinyl), N-alkyl piperidines suchas N-methyl piperidine, piperidone, pyrrolidine (e.g. 1-pyrrolidinyl,2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, pyran(2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran,dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane,tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine, N-ethyl piperazine and N-isopropylpiperazine.

One sub-group of monocyclic non-aromatic heterocyclic groups includesmorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl 3-piperidinyland 4-piperidinyl), piperidone, pyrrolidine (e.g. 1-pyrrolidinyl,2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran,dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane,tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine. In general, preferred non-aromatic heterocyclic groupsinclude piperidine, pyrrolidine, azetidine, morpholine, piperazine andN-alkyl piperazines. A further particular example of a non-aromaticheterocyclic group, which also forms part of the above group ofpreferred non-aromatic heterocyclic groups, is azetidine.

Examples of non-aromatic carbocyclic groups include cycloalkane groupssuch as cyclohexyl and cyclopentyl, cycloalkenyl groups such ascyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well ascyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.

Each of the definitions of carbocyclic and heterocyclic groups in thisspecification may optionally exclude any one or any combination of twoor more of the following moieties:

-   -   substituted or unsubstituted pyridone rings;    -   substituted or unsubstituted pyrrolo[1,2-a]pyrimid-4-ones;    -   substituted or unsubstituted pyrazolones.

Where reference is made herein to carbocyclic and heterocyclic groups,the carbocyclic or heterocyclic ring can, unless the context indicatesotherwise, be unsubstituted or substituted by one or more substituentgroups R¹⁰ selected from halogen, hydroxy, trifluoromethyl, cyano,nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclicand heterocyclic groups having from 3 to 12 ring members; a groupR^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹,S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected fromhydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ringmembers, and a C₁₋₈ hydrocarbyl group optionally substituted by one ormore substituents selected from hydroxy, oxo, halogen, cyano, nitro,carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic andheterocyclic groups having from 3 to 12 ring members and wherein one ormore carbon atoms of the C₁₋₈ hydrocarbyl group may optionally bereplaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;

-   -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR and X² is ═O, ═S or ═NR^(c).

Where the substituent group R¹⁰ comprises or includes a carbocyclic orheterocyclic group, the said carbocyclic or heterocyclic group may beunsubstituted or may itself be substituted with one or more furthersubstituent groups R¹⁰. In one sub-group of compounds of the formula(I), such further substituent groups R¹⁰ may include carbocyclic orheterocyclic groups, which are typically not themselves furthersubstituted. In another sub-group of compounds of the formula (I), thesaid further substituents do not include carbocyclic or heterocyclicgroups but are otherwise selected from the groups listed above in thedefinition of R¹⁰.

The substituents R¹⁰ may be selected such that they contain no more than20 non-hydrogen atoms, for example, no more than 15 non-hydrogen atoms,e.g. no more than 12, or 10, or 9, or 8, or 7, or 6, or 5 non-hydrogenatoms.

Where the carbocyclic and heterocyclic groups have a pair ofsubstituents on adjacent ring atoms, the two substituents may be linkedso as to form a cyclic group. For example, an adjacent pair ofsubstituents on adjacent carbon atoms of a ring may be linked via one ormore heteroatoms and optionally substituted alkylene groups to form afused oxa-, dioxa-, aza-, diaza- or oxa-aza-cycloalkyl group. Examplesof such linked substituent groups include:

Examples of halogen substituents include fluorine, chlorine, bromine andiodine. Fluorine and chlorine are particularly preferred.

In the definition of the compounds of the formula (I) above and as usedhereinafter, the term “hydrocarbyl” is a generic term encompassingaliphatic, alicyclic and aromatic groups having an all-carbon backbone,except where otherwise stated. In certain cases, as defined herein, oneor more of the carbon atoms making up the carbon backbone may bereplaced by a specified atom or group of atoms. Examples of hydrocarbylgroups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl,alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclicaralkyl, aralkenyl and aralkynyl groups. Such groups can beunsubstituted or, where stated, can be substituted by one or moresubstituents as defined herein. The examples and preferences expressedbelow apply to each of the hydrocarbyl substituent groups orhydrocarbyl-containing substituent groups referred to in the variousdefinitions of substituents for compounds of the formula (I) unless thecontext indicates otherwise.

Generally by way of example, the hydrocarbyl groups can have up to eightcarbon atoms, unless the context requires otherwise. Within the sub-setof hydrocarbyl groups having 1 to 8 carbon atoms, particular examplesare C₁₋₆ hydrocarbyl groups, such as C₁₋₄ hydrocarbyl groups (e.g. C₁₋₃hydrocarbyl groups or C₁₋₂ hydrocarbyl groups), specific examples beingany individual value or combination of values selected from C₁, C₂, C₃,C₄, C₅, C₆, C₇ and C₈ hydrocarbyl groups.

The term “alkyl” covers both straight chain and branched chain alkylgroups. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl,2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers. Within thesub-set of alkyl groups having 1 to 8 carbon atoms, particular examplesare C₁₋₆ alkyl groups, such as C₁₋₄ alkyl groups (e.g. C₁₋₃ alkyl groupsor C₁₋₂ alkyl groups).

Examples of cycloalkyl groups are those derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within thesub-set of cycloalkyl groups the cycloalkyl group will have from 3 to 8carbon atoms, particular examples being C₃₋₆ cycloalkyl groups.

Examples of alkenyl groups include, but are not limited to, ethenyl(vinyl), 1-propenyl, 2-propenyl(allyl), isopropenyl, butenyl,buta-1,4-dienyl, pentenyl, and hexenyl. Within the sub-set of alkenylgroups the alkenyl group will have 2 to 8 carbon atoms, particularexamples being C₂₋₆ alkenyl groups, such as C₂₋₄ alkenyl groups.

Examples of cycloalkenyl groups include, but are not limited to,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl andcyclohexenyl. Within the sub-set of cycloalkenyl groups the cycloalkenylgroups have from 3 to 8 carbon atoms, and particular examples are C₃₋₆cycloalkenyl groups.

Examples of alkynyl groups include, but are not limited to, ethynyl and2-propynyl(propargyl) groups. Within the sub-set of alkynyl groupshaving 2 to 8 carbon atoms, particular examples are C₂₋₆ alkynyl groups,such as C₂₋₄ alkynyl groups.

Examples of carbocyclic aryl groups include substituted andunsubstituted phenyl, naphthyl, indane and indene groups.

Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl,aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl,phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl,cyclopropylmethyl and cyclopentenylmethyl groups.

When present, and where stated, a hydrocarbyl group can be optionallysubstituted by one or more substituents selected from hydroxy, oxo,alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C₁₋₄hydrocarbylamino, and monocyclic or bicyclic carbocyclic andheterocyclic groups having from 3 to 12 (typically 3 to 10 and moreusually 5 to 10) ring members. Preferred substituents include halogensuch as fluorine. Thus, for example, the substituted hydrocarbyl groupcan be a partially fluorinated or perfluorinated group such asdifluoromethyl or trifluoromethyl. In one embodiment preferredsubstituents include monocyclic carbocyclic and heterocyclic groupshaving 3-7 ring members.

Where stated, one or more carbon atoms of a hydrocarbyl group mayoptionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ orX¹C(X²)X¹ (or a sub-group thereof) wherein X¹ and X² are as hereinbeforedefined, provided that at least one carbon atom of the hydrocarbyl groupremains. For example, 1, 2, 3 or 4 carbon atoms of the hydrocarbyl groupmay be replaced by one of the atoms or groups listed, and the replacingatoms or groups may be the same or different. In general, the number oflinear or backbone carbon atoms replaced will correspond to the numberof linear or backbone atoms in the group replacing them. Examples ofgroups in which one or more carbon atom of the hydrocarbyl group havebeen replaced by a replacement atom or group as defined above includeethers and thioethers (C replaced by O or S), amides, esters, thioamidesand thioesters (C—C replaced by X¹C(X²) or C(X²)X¹), sulphones andsulphoxides (C replaced by SO or SO₂), amines (C replaced by NR^(c)).Further examples include ureas, carbonates and carbamates (C—C—Creplaced by X¹C(X²)X¹).

Where an amino group has two hydrocarbyl substituents, they may,together with the nitrogen atom to which they are attached, andoptionally with another heteroatom such as nitrogen, sulphur, or oxygen,link to form a ring structure of 4 to 7 ring members.

The definition “R^(a)-R^(b)” as used herein, either with regard tosubstituents present on a carbocyclic or heterocyclic moiety, or withregard to other substituents present at other locations on the compoundsof the formula (I), includes inter alia compounds wherein R^(a) isselected from a bond, O, CO, OC(O), SC(O), NR^(c)C(O), OC(S), SC(S),NR^(c)C(S), OC(NR^(c)), SC(NR^(c)), NR^(c)C(NR^(c)), C(O)O, C(O)S,C(O)NR^(c), C(S)O, C(S)S, C(S) NR^(c), C(NR^(c))O, C(NR^(c))S,C(NR^(c))NR^(c), OC(O)O, SC(O)O, NR^(c)C(O)O, OC(S)O, SC(S)O,NR^(c)C(S)O, OC(NR^(c))O, SC(NR^(c))O, NR^(c)C(NR^(c))O, OC(O)S, SC(O)S,NR^(c)C(O)S, OC(S)S, SC(S)S, NR^(c)C(S)S, OC(NR^(c))S, SC(NR^(c))S,NR^(c)C(NR^(c))S, OC(O)NR^(c), SC(O)NR^(c), NR^(c)C(O)NR^(c),OC(S)NR^(c), SC(S)NR^(c), NR^(c)C(S)NR^(c), OC(NR^(c))NR^(c),SC(NR^(c))NR^(c), NR^(c)C(NR^(c)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c)and NR^(c)SO₂ wherein R^(c) is as hereinbefore defined.

The moiety R^(b) can be hydrogen or it can be a group selected fromcarbocyclic and heterocyclic groups having from 3 to 12 ring members(typically 3 to 10 and more usually from 5 to 10), and a C₁₋₈hydrocarbyl group optionally substituted as hereinbefore defined.Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as setout above.

When R^(a) is O and R^(b) is a C₁₋₈ hydrocarbyl group, R^(a) and R^(b)together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groupsinclude saturated hydrocarbyloxy such as alkoxy (e.g. C₁₋₆ alkoxy, moreusually C₁₋₄ alkoxy such as ethoxy and methoxy, particularly methoxy),cycloalkoxy (e.g. C₃₋₆ cycloalkoxy such as cyclopropyloxy,cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkyalkoxy(e.g. C₃₋₆ cycloalkyl-C₁₋₂ alkoxy such as cyclopropylmethoxy).

The hydrocarbyloxy groups can be substituted by various substituents asdefined herein. For example, the alkoxy groups can be substituted byhalogen (e.g. as in difluoromethoxy and trifluoromethoxy), hydroxy (e.g.as in hydroxyethoxy), C₁₋₂ alkoxy (e.g. as in methoxyethoxy),hydroxy-C₁₋₂ alkyl (as in hydroxyethoxyethoxy) or a cyclic group (e.g. acycloalkyl group or non-aromatic heterocyclic group as hereinbeforedefined). Examples of alkoxy groups bearing a non-aromatic heterocyclicgroup as a substituent are those in which the heterocyclic group is asaturated cyclic amine such as morpholine, piperidine, pyrrolidine,piperazine, C₁₋₄-alkyl-piperazines, C₃₋₇-cycloalkyl-piperazines,tetrahydropyran or tetrahydrofuran and the alkoxy group is a C₁₋₄ alkoxygroup, more typically a C₁₋₃ alkoxy group such as methoxy, ethoxy orn-propoxy.

Alkoxy groups may be substituted by, for example, a monocyclic groupsuch as pyrrolidine, piperidine, morpholine and piperazine andN-substituted derivatives thereof such as N-benzyl, N—C₁₋₄ acyl andN—C₁₋₄ alkoxycarbonyl. Particular examples include pyrrolidinoethoxy,piperidinoethoxy and piperazinoethoxy.

When R^(a) is a bond and R^(b) is a C₁₋₈ hydrocarbyl group, examples ofhydrocarbyl groups R^(a)-R^(b) are as hereinbefore defined. Thehydrocarbyl groups may be saturated groups such as cycloalkyl and alkyland particular examples of such groups include methyl, ethyl andcyclopropyl. The hydrocarbyl (e.g. alkyl) groups can be substituted byvarious groups and atoms as defined herein. Examples of substitutedalkyl groups include alkyl groups substituted by one or more halogenatoms such as fluorine and chlorine (particular examples includingbromoethyl, chloroethyl, difluoromethyl, 2,2,2-trifluoroethyl andperfluoroalkyl groups such as trifluoromethyl), or hydroxy (e.g.hydroxymethyl and hydroxyethyl), C₁₋₈ acyloxy (e.g. acetoxymethyl andbenzyloxymethyl), amino and mono- and dialkylamino (e.g. aminoethyl,methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl andtert-butylaminomethyl), alkoxy (e.g. C₁₋₂ alkoxy such as methoxy—as inmethoxyethyl), and cyclic groups such as cycloalkyl groups, aryl groups,heteroaryl groups and non-aromatic heterocyclic groups as hereinbeforedefined).

Particular examples of alkyl groups substituted by a cyclic group arethose wherein the cyclic group is a saturated cyclic amine such asmorpholine, piperidine, pyrrolidine, piperazine, C₁₋₄-alkyl-piperazines,C₃₋₇-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and thealkyl group is a C₁₋₄ alkyl group, more typically a C₁₋₃ alkyl groupsuch as methyl, ethyl or n-propyl. Specific examples of alkyl groupssubstituted by a cyclic group include pyrrolidinomethyl,pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl,piperidinylmethyl, piperazinomethyl and N-substituted forms thereof asdefined herein.

Particular examples of alkyl groups substituted by aryl groups andheteroaryl groups include benzyl, phenethyl and pyridylmethyl groups.

When R^(a) is SO₂NR^(c), R^(b) can be, for example, hydrogen or anoptionally substituted C₁₋₈ hydrocarbyl group, or a carbocyclic orheterocyclic group. Examples of R^(a)-R^(b) where R^(a) is SO₂NR^(c)include aminosulphonyl, C₁₋₄ alkylaminosulphonyl and di-C₁₋₄alkylaminosulphonyl groups, and sulphonamides formed from a cyclic aminogroup such as piperidine, morpholine, pyrrolidine, or an optionallyN-substituted piperazine such as N-methyl piperazine.

Examples of groups R^(a)-R^(b) where R^(a) is SO₂ includealkylsulphonyl, heteroarylsulphonyl and arylsulphonyl groups,particularly monocyclic aryl and heteroaryl sulphonyl groups. Particularexamples include methylsulphonyl, phenylsulphonyl and toluenesulphonyl.

When R^(a) is NR^(c), R^(b) can be, for example, hydrogen or anoptionally substituted C₁₋₈ hydrocarbyl group, or a carbocyclic orheterocyclic group. Examples of R^(a)-R^(b) where R^(a) is NR includeamino, C₁₋₄ alkylamino (e.g. methylamino, ethylamino, propylamino,isopropylamino, tert-butylamino), di-C₁₋₄ alkylamino (e.g. dimethylaminoand diethylamino) and cycloalkylamino (e.g. cyclopropylamino,cyclopentylamino and cyclohexylamino).

Specific Embodiments of and Preferences for A, E, R¹ to R⁵ and R⁹

The Group “A”

In formula (I), A is a saturated hydrocarbon linker group containingfrom 1 to 7 carbon atoms, the linker group having a maximum chain lengthof 5 atoms extending between R¹ and NR²R³ and a maximum chain length of4 atoms extending between E and NR²R³. Within these constraints, themoieties E and R¹ can each be attached at any location on the group A.

The term “maximum chain length” as used herein refers to the number ofatoms lying directly between the two moieties in question, and does nottake into account any branching in the chain or any hydrogen atoms thatmay be present. For example, in the structure A shown below:

the chain length between R¹ and NR²R³ is 3 atoms whereas the chainlength between E and NR²R³ is 2 atoms.

In general it is presently preferred that the linker group has a maximumchain length of 3 atoms (for example 1 or 2 atoms).

In one embodiment, the linker group has a chain length of 1 atomextending between R¹ and NR²R³.

In another embodiment, the linker group has a chain length of 2 atomsextending between R¹ and NR²R³.

In a further embodiment, the linker group has a chain length of 3 atomsextending between R¹ and NR²R³.

It is preferred that the linker group has a maximum chain length of 3atoms extending between E and NR²R³.

In one particularly preferred group of compounds, the linker group has achain length of 2 or 3 atoms extending between R¹ and NR²R³ and a chainlength of 2 or 3 atoms extending between E and NR²R³.

One of the carbon atoms in the linker group may optionally be replacedby an oxygen or nitrogen atom.

When present, the nitrogen atom may be linked directly to the group E.

In one embodiment, the carbon atom to which the group R¹ is attached isreplaced by an oxygen atom.

In another embodiment, R¹ and E are attached to the same carbon atom ofthe linker group, and a carbon atom in the chain extending between E andNR²R³ is replaced by an oxygen atom.

When a nitrogen atom or oxygen atom are present, it is preferred thatthe nitrogen or oxygen atom and the NR²R³ group are spaced apart by atleast two intervening carbon atoms.

In one particular group of compounds within formula (I), the linker atomlinked directly to the group E is a carbon atom and the linker group Ahas an all-carbon skeleton.

The carbon atoms of the linker group A may optionally bear one or moresubstituents selected from oxo, fluorine and hydroxy, provided that thehydroxy group is not located at a carbon atom α with respect to theNR²R³ group, and provided also that the oxo group is located at a carbonatom α with respect to the NR²R³ group. Typically, the hydroxy group, ifpresent, is located at a position P with respect to the NR²R³ group. Ingeneral, no more than one hydroxy group will be present. Where fluorineis present, it may be present as a single fluorine substituent or may bepresent in a difluoromethylene or trifluoromethyl group, for example. Inone embodiment, a fluorine atom is located at a position P with respectto the NR²R³ group.

It will be appreciated that that when an oxo group is present at thecarbon atom adjacent the NR²R³ group, the compound of the formula (I)will be an amide.

In one embodiment of the invention, no fluorine atoms are present in thelinker group A.

In another embodiment of the invention, no hydroxy groups are present inthe linker group A.

In a further embodiment, no oxo group is present in the linker group A.

In one group of compounds of the formula (I) neither hydroxy groups norfluorine atoms are present in the linker group A, e.g. the linker groupA is unsubstituted.

Preferably, when a carbon atom in the linker group A is replaced by anitrogen atom, the group A bears no more than one hydroxy substituentand more preferably bears no hydroxy substituents.

When there is a chain length of four atoms between E and NR²R³, it ispreferred that the linker group A contains no nitrogen atoms and morepreferably has an all carbon skeleton.

In order to modify the susceptibility of the compounds to metabolicdegradation in vivo, the linker group A can have a branchedconfiguration at the carbon atom attached to the NR²R³ group. Forexample, the carbon atom attached to the NR²R³ group can be attached toa pair of gem-dimethyl groups.

In one particular group of compounds of the formula (I), the portionR¹-A-NR²R³ of the compound is represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—W—O_(b)—(CH₂)_(n)—(CR⁶R⁷)_(P)—NR²R³ wherein G isNH, NMe or O; W is attached to the group E and is selected from(CH₂)_(j)—CR²⁰, (CH₂)_(j)—N and (NH)_(j)—CH; b is 0 or 1, j is 0 or 1, kis 0 or 1, m is 0 or 1, n is 0, 1, 2, or 3 and p is 0 or 1; the sum of band k is 0 or 1; the sum of j, k, m, n and p does not exceed 4; R⁶ andR⁷ are the same or different and are selected from methyl and ethyl, orCR⁶R⁷ forms a cyclopropyl group; and R²⁰ is selected from hydrogen,methyl, hydroxy and fluorine;

In another sub-group of compounds of the formula (I), the portionR¹-A-NR²R³ of the compound is represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—X—(CH₂)_(n)—(CR⁶R⁷)_(p)—NR²R³ wherein G is NH, NMeor O; X is attached to the group E and is selected from (CH₂)_(j)—CH,(CH₂)_(j)—N and (NH)_(j)—CH; j is 0 or 1, k is 0 or 1, m is 0 or 1, n is0, 1, 2, or 3 and p is 0 or 1, and the sum of j, k, m, n and p does notexceed 4; and R⁶ and R⁷ are the same or different and are selected frommethyl and ethyl, or CR⁶R⁷ forms a cyclopropyl group.

A particular group CR⁶R⁷ is C(CH₃)₂.

Preferably X is (CH₂)_(j)—CH.

Particular configurations where the portion R¹-A-NR²R³ of the compoundis represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—X—(CH₂)_(n)—(CR⁶R⁷)_(p)—NR²R³ are those wherein:

-   -   k is, m is 0 or 1, n is 0, 1, 2 or 3 and p is 0.    -   k is 0, m is 0 or 1, n is 0, 1 or 2 and p is 1.    -   X is (CH₂)_(j)—CH, k is 1, m is 0, n is 0, 1, 2 or 3 and p is 0.    -   X is (CH₂)_(j)—CH, k is 1, m is 0, n is 0, 1 or 2 and p is 1.    -   X is (CH₂)_(j)—CH, G is O, k is 1, m is 0, n is 0, 1, 2 or 3 and        p is 0.

Particular configurations wherein the portion R¹-A-NR²R³ of the compoundis represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—W—O_(b)—(CH₂)_(n)—(CR⁶R⁷)_(p)—NR²R³ are thosewherein:

-   -   k is 0, m is 0, W is (CH₂)_(j)—CR²⁰, j is 0, R²⁰ is hydrogen, b        is 1, n is 2 and p is 0.    -   k is 0, m is 0, W is (CH₂)_(j)—CR²⁰, j is 0, R²⁰ is hydroxy, b        is 0, n is 1 and p is 0.    -   k is 0, m is 0, W is (CH₂)_(j)—CR²⁰, j is 0, R²⁰ is methyl, b is        0, n is 1 and p is 0.    -   k is 0, m is 0, W is (CH₂)_(j)—CR²⁰, j is 0, R²⁰ is fluorine, b        is 0, n is 1 and p is 0.

In one preferred configuration, the portion R¹-A-NR²R³ of the compoundis represented by the formula R¹—X—(CH₂)_(n)—NR²R³ wherein X is attachedto the group E and is a group CH, and n is 2.

Particular examples of the linker group A, together with their points ofattachment to the groups R¹, E and NR²R³, are shown in Table 1 below.

TABLE 1

A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

Currently preferred groups include A1, A2, A3, A6, A10, A11, A22 andA23.

One particular set of groups includes A1, A2, A3, A10 and A11.

A further particular set of groups includes A2 and A11.

Another particular set of groups includes A6, A22 and A23.

A further set of groups includes A1, A2 and A3.

In group A2, the asterisk designates a chiral centre. Compounds havingthe R configuration at this chiral centre represent one preferredsub-group of compounds of the invention.

R¹

The group R¹ is an aryl or heteroaryl group and may be selected from thelist of such groups set out in the section headed General Preferencesand Definitions.

R¹ can be monocyclic or bicyclic and, in one preferred embodiment, ismonocyclic. Particular examples of monocyclic aryl and heteroaryl groupsare six membered aryl and heteroaryl groups containing up to 2 nitrogenring members, and five membered heteroaryl groups containing up to 3heteroatom ring members selected from O, S and N.

Examples of such groups include phenyl, naphthyl, thienyl, furan,pyrimidine and pyridine, with phenyl being presently preferred.

The group R¹ can be unsubstituted or substituted by up to 5substituents, and examples of substituents are those listed in group R¹⁰above.

Particular substituents include hydroxy; C₁₋₄ acyloxy; fluorine;chlorine; bromine; trifluoromethyl; cyano; CONH₂; nitro; C₁₋₄hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionally substituted by C₁₋₂alkoxy, carboxy or hydroxy; C₁₋₄ acylamino; benzoylamino;pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl;piperazinocarbonyl; five and six membered heteroaryl and heteroaryloxygroups containing one or two heteroatoms selected from N, O and S;phenyl; phenyl-C₁₋₄ alkyl; phenyl-C₁₋₄ alkoxy; heteroaryl-C₁₋₄ alkyl;heteroaryl-C₁₋₄ alkoxy and phenoxy, wherein the heteroaryl,heteroaryloxy, phenyl, phenyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkoxy,heteroaryl-C₁₋₄ alkyl, heteroaryl-C₁₋₄ alkoxy and phenoxy groups areeach optionally substituted with 1, 2 or 3 substituents selected fromC₁₋₂ acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano,CONH₂, C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl each optionallysubstituted by methoxy or hydroxy.

Preferred substituents include hydroxy; C₁₋₄ acyloxy; fluorine;chlorine; bromine; trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄hydrocarbyl each optionally substituted by C₁₋₂ alkoxy or hydroxy; C₁₋₄acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl;morpholinocarbonyl; piperazinocarbonyl; five and six membered heteroarylgroups containing one or two heteroatoms selected from N, O and S, theheteroaryl groups being optionally substituted by one or more C₁₋₄ alkylsubstituents; phenyl; pyridyl; and phenoxy wherein the phenyl, pyridyland phenoxy groups are each optionally substituted with 1, 2 or 3substituents selected from C₁₋₂ acyloxy, fluorine, chlorine, bromine,trifluoromethyl, cyano, C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl eachoptionally substituted by methoxy or hydroxy.

In one sub-group of compounds, the substituents for R¹ are chosen fromhydroxy; C₁₋₄ acyloxy; fluorine; chlorine; bromine; trifluoromethyl;cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionallysubstituted by C₁₋₂ alkoxy or hydroxy.

Although up to 5 substituents may be present, more typically there are0, 1, 2, 3 or 4 substituents, preferably 0, 1, 2 or 3, and morepreferably 0, 1 or 2.

In one embodiment, the group R¹ is unsubstituted or substituted by up to5 substituents selected from hydroxy; C₁₋₄ acyloxy; fluorine; chlorine;bromine; trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄hydrocarbyl each optionally substituted by C₁₋₂ alkoxy or hydroxy.

In a further embodiment, the group R¹ can have one or two substituentsselected from hydroxy, fluorine, chlorine, cyano, phenyloxy,pyrazinyloxy, benzyloxy, methyl and methoxy.

In another embodiment, the group R¹ can have one or two substituentsselected from fluorine, chlorine, trifluoromethyl, methyl and methoxy.

When R¹ is a phenyl group, particular examples of substituentcombinations include mono-chlorophenyl and dichlorophenyl.

Further examples of substituent combinations include those wherein R¹ ishydroxyphenyl, fluorochlorophenyl, cyanophenyl, methoxyphenyl,methoxychlorophenyl, fluorophenyl, difluorophenyl, phenoxyphenyl,pyrazinyloxyphenyl or benzyloxyphenyl.

When R¹ is a six membered aryl or heteroaryl group, a substituent mayadvantageously be present at the para position on the six-membered ring.Where a substituent is present at the para position, it is preferablylarger in size than a fluorine atom.

R² and R³

In one group of compounds of the formula (I), R² and R³ areindependently selected from hydrogen, C₁₋₄ hydrocarbyl and C₁₋₄ acylwherein the hydrocarbyl and acyl moieties are optionally substituted byone or more substituents selected from fluorine, hydroxy, amino,methylamino, dimethylamino and methoxy.

When the hydrocarbyl moiety is substituted by a hydroxy, amino,methylamino, dimethylamino or methoxy group, typically there are atleast two carbon atoms between the substituent and the nitrogen atom ofthe group NR²R³. Particular examples of substituted hydrocarbyl groupsare hydroxyethyl and hydroxypropyl.

In another group of compounds of the invention, R² and R³ areindependently selected from hydrogen, C₁₋₄ hydrocarbyl and C₁₋₄ acyl.

Typically the hydrocarbyl group, whether substituted or unsubstituted,is an alkyl group, more usually a C₁, C₂ or C₃ alkyl group, andpreferably a methyl group. In one particular sub-group of compounds, R²and R³ are independently selected from hydrogen and methyl and henceNR²R³ can be an amino, methylamino or dimethylamino group. In oneparticular embodiment, NR²R³ can be an amino group. In anotherparticular embodiment, NR²R³ can be a methylamino group.

In an alternative embodiment, the C₁₋₄ hydrocarbyl group can be acyclopropyl, cyclopropylmethyl or cyclobutyl group.

In another group of compounds, R² and R³ together with the nitrogen atomto which they are attached form a cyclic group selected from animidazole group and a saturated monocyclic heterocyclic group having 4-7ring members and optionally containing a second heteroatom ring memberselected from O and N.

In a further group of compounds, R² and R³ together with the nitrogenatom to which they are attached form a saturated monocyclic heterocyclicgroup having 4-7 ring members and optionally containing a secondheteroatom ring member selected from O and N.

The saturated monocyclic heterocyclic group can be unsubstituted orsubstituted by one or more substituents R¹⁰ as defined above in theGeneral Preferences and Definitions section of this application.Typically, however, any substituents on the heterocyclic group will berelatively small substituents such as C₁₋₄ hydrocarbyl (e.g. methyl,ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, sec-butyl andtert-butyl), fluorine, chlorine, hydroxy, amino, methylamino, ethylaminoand dimethylamino. Particular substituents are methyl groups.

The saturated monocyclic ring can be an azacycloalkyl group such as anazetidine, pyrrolidine, piperidine or azepane ring, and such rings aretypically unsubstituted. Alternatively, the saturated monocyclic ringcan contain an additional heteroatom selected from O and N, and examplesof such groups include morpholine and piperazine. Where an additional Natom is present in the ring, this can form part of an NH group or anN—C₁₋₄alkyl group such as an N-methyl, N-ethyl, N-propyl or N-isopropylgroup.

Where NR²R³ forms an imidazole group, the imidazole group can beunsubstituted or substituted, for example by one or more relativelysmall substituents such as C₁₋₄ hydrocarbyl (e.g. methyl, ethyl, propyl,cyclopropyl and butyl), fluorine, chlorine, hydroxy, amino, methylamino,ethylamino and dimethylamino. Particular substituents are methyl groups.

In a further group of compounds, one of R² and R³ together with thenitrogen atom to which they are attached and one or more atoms from thelinker group A form a saturated monocyclic heterocyclic group having 4-7ring members and optionally containing a second heteroatom ring memberselected from O and N.

Examples of such compounds include compounds wherein NR²R³ and A form aunit of the formula:

where t and u are each 0, 1, 2 or 3 provided that the sum of t and ufalls within the range of 2 to 4.

Further examples of such compounds include compounds wherein NR²R³ and Aform a cyclic group of the formula:

where v and w are each 0, 1, 2 or 3 provided that the sum of v and wfalls within the range of 2 to 5. Particular examples of cycliccompounds are those in which v and w are both 2.

Further examples of such compounds include compounds wherein NR²R³ and Aform a cyclic group of the formula:

where x and w are each 0, 1, 2 or 3 provided that the sum of x and wfalls within the range of 2 to 4. Particular examples of cycliccompounds are those in which x is 2 and w is 1.R⁴

In formula (I), R⁴ is selected from hydrogen, halogen, C₁₋₅ saturatedhydrocarbyl, C₁₋₅ saturated hydrocarbyloxy, cyano, and CF₃.

More typically, R⁴ is selected from hydrogen, halogen, C₁₋₅ saturatedhydrocarbyl, cyano and CF₃. Preferred values for R⁴ include hydrogen andmethyl. In a particular embodiment, R⁴ is hydrogen.

R⁵

In formula (I), R⁵ is selected from hydrogen, halogen, C₁₋₅ saturatedhydrocarbyl, C₁₋₅ saturated hydrocarbyloxy, cyano, CONH₂, CONHR⁹, CF₃,NH₂, NHCOR⁹ and NHCONHR⁹; NHCONHR⁹ where R⁹ is a group R^(9a) or(CH₂)R^(9a), wherein R^(9a) is an optionally substituted monocyclic orbicyclic group which may be carbocyclic or heterocyclic.

Examples of carbocyclic and heterocyclic groups are set out above in theGeneral Preferences and Definitions section.

Typically the carbocyclic and heterocyclic groups are monocyclic.

Preferably the carbocyclic and heterocyclic groups are aromatic.

Particular examples of the group R⁹ are optionally substituted phenyl orbenzyl.

Preferably, R⁵ is selected from selected from hydrogen, halogen, C₁₋₅saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ andNHCONHR⁹ where R⁹ is optionally substituted phenyl or benzyl.

More preferably, R⁵ is selected from selected from hydrogen, halogen,C₁₋₅ saturated hydrocarbyl, cyano, CF₃, NH₂, NHCOR⁹ and NHCONHR⁹ whereR⁹ is optionally substituted phenyl or benzyl.

The group R⁹ is typically unsubstituted phenyl or benzyl, or phenyl orbenzyl substituted by 1, 2 or 3 substituents selected from halogen;hydroxy; trifluoromethyl; cyano; carboxy; C₁₋₄alkoxycarbonyl; C₁₋₄acyloxy; amino; mono- or di-C₁₋₄ alkylamino; C₁₋₄ alkyl optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy; C₁₋₄ alkoxy optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy; phenyl, five and sixmembered heteroaryl groups containing up to 3 heteroatoms selected fromO, N and S; and saturated carbocyclic and heterocyclic groups containingup to 2 heteroatoms selected from O, S and N.

Particular examples of the moiety R⁵ include hydrogen, fluorine,chlorine, bromine, methyl, ethyl, hydroxyethyl, methoxymethyl, cyano,CF₃, NH₂, NHCOR^(9b) and NHCONHR^(9b) where R^(9b) is phenyl or benzyloptionally substituted by hydroxy, C₁₋₄ acyloxy, fluorine, chlorine,bromine, trifluoromethyl, cyano, C₁₋₄ hydrocarbyloxy (e.g. alkoxy) andC₁₋₄ hydrocarbyl (e.g. alkyl) optionally substituted by C₁₋₂ alkoxy orhydroxy.

Preferred examples of R⁵ include hydrogen, methyl and cyano. PreferablyR⁵ is hydrogen or methyl.

The Group “E”

In formula (I), E is a monocyclic or bicyclic carbocyclic orheterocyclic group and can be selected from the groups set out above inthe section headed General Preferences and Definitions.

Preferred groups E are monocyclic and bicyclic aryl and heteroarylgroups and, in particular, groups containing a six membered aromatic orheteroaromatic ring such as a phenyl, pyridine, pyrazine, pyridazine orpyrimidine ring, more particularly a phenyl, pyridine, pyrazine orpyrimidine ring, and more preferably a pyridine or phenyl ring.

Examples of bicyclic groups include benzo-fused and pyrido-fused groupswherein the group A and the pyrazole ring are both attached to thebenzo- or pyrido-moiety.

In one embodiment, E is a monocyclic group.

Particular examples of monocyclic groups include monocyclic aryl andheteroaryl groups such as phenyl, thiophene, furan, pyrimidine, pyrazineand pyridine, phenyl being presently preferred.

One subset of monocyclic aryl and heteroaryl groups comprises phenyl,thiophene, furan, pyrimidine and pyridine.

Examples of non-aromatic monocyclic groups include cycloalkanes such ascyclohexane and cyclopentane, and nitrogen-containing rings such aspiperazine and piperazone.

It is preferred that the group A and the pyrazole group are not attachedto adjacent ring members of the group E. For example, the pyrazole groupcan be attached to the group E in a meta or para relative orientation.Examples of such groups E include 1,4-phenylene, 1,3-phenylene,2,5-pyridylene and 2,4-pyridylene, 1,4-piperazinyl, and 1,4-piperazonyl.Further examples include 1,3-disubstituted five membered rings.

The groups E can be unsubstituted or can have up to 4 substituents R⁸which may be selected from the group R¹⁰ as hereinbefore defined. Moretypically however, the substituents R⁸ are selected from hydroxy; oxo(when E is non-aromatic); halogen (e.g. chlorine and bromine);trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy optionally substituted byC₁₋₂ alkoxy or hydroxy; and C₁₋₄ hydrocarbyl optionally substituted byC₁₋₂ alkoxy or hydroxy.

Preferably there are 0-3 substituents, more preferably 0-2 substituents,for example 0 or 1 substituent. In one embodiment, the group E isunsubstituted.

E may be other than:

-   -   a substituted pyridone group;    -   a substituted thiazole group;    -   a substituted or unsubstituted pyrazole or pyrazolone group;    -   a substituted or unsubstituted bicyclic fused pyrazole group;    -   a phenyl ring fused to a thiophene ring or a six membered        nitrogen-containing heteroaryl ring fused to a thiophene ring;    -   a substituted or unsubstituted piperazine group;

The group E can be an aryl or heteroaryl group having five or sixmembers and containing up to three heteroatoms selected from O, N and S,the group E being represented by the formula:

where * denotes the point of attachment to the pyrazole group, and “a”denotes the attachment of the group A,r is 0, 1 or 2;U is selected from N and CR^(12a); andV is selected from N and CR^(12b); where R^(12a) and R^(12b) are thesame or different and each is hydrogen or a substituent containing up toten atoms selected from C, N, O, F, Cl and S provided that the totalnumber of non-hydrogen atoms present in R^(12a) and R^(12b) togetherdoes not exceed ten;or R^(12a) and R^(12b) together with the carbon atoms to which they areattached form an unsubstituted five or six membered saturated orunsaturated ring containing up to two heteroatoms selected from O and N;andR¹⁰ is as hereinbefore defined.

In one preferred group of compounds, E is a group:

where * denotes the point of attachment to the pyrazole group, and “a”denotes the attachment of the group A;P, Q and T are the same or different and are selected from N, CH andNCR¹⁰, provided that the group A is attached to a carbon atom; and U, Vand R¹⁰ are as hereinbefore defined.

Examples of R^(12a) and R^(12b) include hydrogen and substituent groupsR¹⁰ as hereinbefore defined having no more than ten non-hydrogen atoms.Particular examples of R^(12a) and R^(12b) include methyl, ethyl,propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, fluorine,chlorine, methoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl,methoxymethyl, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethyl,cyano, amino, methylamino, dimethylamino, CONH₂, CO₂Et, CO₂H, acetamido,azetidinyl, pyrrolidino, piperidine, piperazino, morpholino,methylsulphonyl, aminosulphonyl, mesylamino and trifluoroacetamido.

Preferably, when U is CR^(12a) and/or V is CR^(12b) the atoms or groupsin R^(12a) and R^(12b) that are directly attached to the carbon atomring members C are selected from H, O (e.g. as in methoxy), NH (e.g. asin amino and methylamino) and CH₂ (e.g. as in methyl and ethyl).

Particular examples of the linker group E, together with their points ofattachment to the group A (a) and the pyrazole ring (*) are shown inTable 2 below.

TABLE 2

B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

In the table, the substituent group R¹³ is selected from methyl,chlorine, fluorine and trifluoromethyl.

The following optional exclusions may apply to the definition of E inany of formulae (I), (Ia), (Ib), (II), (III), (IV) and (V) and anysub-groups or sub-definitions thereof as defined herein:

-   -   E may be other than a phenyl group having a sulphur atom        attached to the position para with respect to the pyrazole        group.    -   E may be other than a substituted or unsubstituted        benzimidazole, benzoxazole or benzthiazole group.

One sub-group of compounds of the formula (I) has the general formula(II):

wherein the group A is attached to the meta or para position of thebenzene ring, q is 0-4; R¹, R², R³, R⁴ and R⁵ are as defined herein inrespect of formula (I) and sub-groups, examples and preferences thereof;and R⁸ is a substituent group as hereinbefore defined. In formula (II),q is preferably 0, 1 or 2, more preferably 0 or 1 and most preferably 0.Preferably the group A is attached to the para position of the benzenering.

Within formula (II), one particular sub-group of compounds of theinvention is represented by the formula (III):

where A′ is the residue of the group A and R¹ to R⁵ are as definedherein.

Within formula (III), one preferred group of compounds is presented bythe formula (IV):

wherein z is 0, 1 or 2, R²⁰ is selected from hydrogen, methyl, hydroxyand fluorine and R¹ to R⁵ are as defined herein, provided that when z is0, R²⁰ is other than hydroxy.

Another group of compounds within formula (III) is represented byformula (V):

wherein and R¹ and R³ to R⁵ are as defined herein.

In formula (V), R³ is preferably selected from hydrogen and C₁₋₄hydrocarbyl, for example C₁₋₄ alkyl such as methyl, ethyl and isopropyl.More preferably R³ is hydrogen.

In each of formulae (II) to (V), R¹ is preferably an optionallysubstituted phenyl group as defined herein.

In another sub-group of compounds of the invention, A is a saturatedhydrocarbon linker group containing from 1 to 7 carbon atoms, the linkergroup having a maximum chain length of 5 atoms extending between R¹ andNR²R³ and a maximum chain length of 4 atoms extending between E andNR²R³, wherein one of the carbon atoms in the linker group mayoptionally be replaced by an oxygen or nitrogen atom; and wherein thecarbon atoms of the linker group A may optionally bear one or moresubstituents selected from fluorine and hydroxy, provided that thehydroxy group when present is not located at a carbon atom α withrespect to the NR²R³ group; and

R⁵ is selected from selected from hydrogen, C₁₋₅ saturated hydrocarbyl,cyano, CONH₂, CF₃, NH₂, NHCOR⁹ and NHCONHR⁹.

For the avoidance of doubt, it is to be understood that each general andspecific preference, embodiment and example of the groups R¹ may becombined with each general and specific preference, embodiment andexample of the groups R² and/or R³ and/or R⁴ and/or R⁵ and/or R⁹ andthat all such combinations are embraced by this application.

The various functional groups and substituents making up the compoundsof the formula (I) are typically chosen such that the molecular weightof the compound of the formula (I) does not exceed 1000. More usually,the molecular weight of the compound will be less than 750, for exampleless than 700, or less than 650, or less than 600, or less than 550.More preferably, the molecular weight is less than 525 and, for example,is 500 or less.

Particular compounds of the invention are as illustrated in the examplesbelow and are selected from:

-   2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile;-   2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine;-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   2-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine;-   3-phenyl-2-[3-(H-pyrazol-4-yl)-phenyl]-propylamine;-   3-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   {3-(chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   {3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   {3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide;-   3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-(4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-(4-chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-4-phenyl-piperidine;-   dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine    (R);-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine    (S);-   4-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-morpholine;-   4-{4-[1-(4-chloro-phenyl)-2-pyrrolidin-1-yl-ethyl]-phenyl}-1H-pyrazole;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-amine;-   dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;-   {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;-   {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R);-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S);-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;-   1-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperazine;-   1-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperidine;-   4-{4-[2-azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole;-   1-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   2-(4-chloro-phenyl)-N-methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;-   N-methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-ethyl-amine;-   4-{4-[1-(4-chloro-phenyl)-2-imidazol-1-yl-ethyl]-phenyl}-1H-pyrazole;-   methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;-   {2-(4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;-   methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;-   2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine;-   4-{4-[1-(4-chloro-phenyl)-3-pyrrolidin-1-yl-propyl]-phenyl}-1H-pyrazole;-   4-{4-[3-azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-phenyl}-1H-pyrazole;-   methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-amine;-   dimethyl-(4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenyl)-amine;-   {3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl}-1H-pyrazole-3-carbonitrile;-   3-(4-phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;-   1-methyl-4-{phenyl-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-[1,4]diazepane;-   {3-(3-chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine;-   4-{4-[1-(4-chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1H-pyrazole;-   4-[4-(3-imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1H-pyrazole;-   4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenol;-   1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;-   {2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   {2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   4-[4-(2-methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-[4-(3-methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide;-   2-(4-{2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamide;-   {2-(3-chloro-phenoxy)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   3-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol;-   2-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol;-   3-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol;-   2-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol;-   {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethyl-amine;-   methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-amine;-   4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol;-   3-(4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   4-(4-chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidine;-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine;-   (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic    acid;-   (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic    acid, methyl ester;-   4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;-   2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;-   4-(3,4-dichloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-(4-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzoic acid;-   4-[4-(1H-pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl;-   3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   2-methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;-   2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   3-(3,4-dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-propylamine;-   2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   4-(2-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;-   2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   {2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   4-{4-[2-azetidin-1-yl-1-(4-chloro-phenoxy)-ethyl]-phenyl}-1H-pyrazole;-   3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   {3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;    and-   C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine;    and salts, solvates, tautomers and N-oxides thereof.

In one embodiment, the compound of the formula (I) is selected from thegroup consisting of:

-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine    (R);-   4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;    and-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine.

A further subset of compounds of the formula (I) consists of

-   4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R    isomer);    and salts, solvates, tautomers and N-oxides thereof.    Salts, Solvates, Tautomers, Isomers, N-Oxides, Esters, Prodrugs and    Isotopes

In this section, as in all other sections of this application, unlessthe context indicates otherwise, references to formula (I) includedreferences to formulae (Ia), (Ib), (II), (III), (IV) and (V) and allother sub-groups, preferences and examples thereof as defined herein.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms thereof, for example,as discussed below.

Many compounds of the formula (I) can exist in the form of salts, forexample acid addition salts or, in certain cases salts of organic andinorganic bases such as carboxylate, sulphonate and phosphate salts. Allsuch salts are within the scope of this invention, and references tocompounds of the formula (I) include the salt forms of the compounds. Asin the preceding sections of this application, all references to formula(I) should be taken to refer also to formula (II) and sub-groups thereofunless the context indicates otherwise.

Salt forms may be selected and prepared according to methods describedin Pharmaceutical Salts: Properties, Selection, and Use, P. HeinrichStahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8,Hardcover, 388 pages, August 2002. For example, acid addition salts maybe prepared by dissolving the free base in an organic solvent in which agiven salt form is insoluble or poorly soluble and then adding therequired acid in an appropriate solvent so that the salt precipitatesout of solution.

Acid addition salts may be formed with a wide variety of acids, bothinorganic and organic. Examples of acid addition salts include saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric,ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic,glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic),α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic,isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic,naphthalenesulphonic (e.g. naphthalene-2-sulphonic),naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic,L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic,toluenesulphonic (e.g. p-toluenesulphonic), undecylenic and valericacids, as well as acylated amino acids and cation exchange resins.

One particular group of acid addition salts includes salts formed withhydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulphonic,toluenesulphonic, methanesulphonic, ethanesulphonic,naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic,glucuronic and lactobionic acids.

Another group of acid addition salts includes salts formed from acetic,adipic, ascorbic, aspartic, citric, DL-Lactic, fumaric, gluconic,glucuronic, hippuric, hydrochloric, glutamic, DL-malic,methanesulphonic, sebacic, stearic, succinic and tartaric acids.

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed. In strongeracids, the basic pyrazole nitrogen, as well as the nitrogen atom in thegroup NR²R³, may take part in salt formation. For example, where theacid has a pKa of less than about 3 (e.g. an acid such as hydrochloricacid, sulphuric acid or trifluoroacetic acid), the compounds of theinvention will typically form salts with 2 molar equivalents of theacid.

If the compound is anionic, or has a functional group which may beanionic (e.g., —COOH may be —COO⁻), then a salt may be formed with asuitable cation. Examples of suitable inorganic cations include, but arenot limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthcations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺, Examplesof suitable organic cations include, but are not limited to, ammoniumion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺, NH₂R²⁺,NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammonium ions arethose derived from: ethylamine, diethylamine, dicyclohexylamine,triethylamine, butylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline,meglumine, and tromethamine, as well as amino acids, such as lysine andarginine. An example of a common quaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds of the formula (I) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (I).

Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide.

Where a compound contains several amine functions, one or more than onenitrogen atom may be oxidised to form an N-oxide. Particular examples ofN-oxides are the N-oxides of a tertiary amine or a nitrogen atom of anitrogen-containing heterocycle.

N-Oxides can be formed by treatment of the corresponding amine with anoxidizing agent such as hydrogen peroxide or a per-acid (e.g. aperoxycarboxylic acid), see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages. Moreparticularly, N-oxides can be made by the procedure of L. W. Deady (Syn.Comm. 1977, 7, 509-514) in which the amine compound is reacted withm-chloroperoxybenzoic acid (MCPBA), for example, in an inert solventsuch as dichloromethane.

Compounds of the formula (I) may exist in a number of differentgeometric isomeric, and tautomeric forms and references to compounds ofthe formula (I) include all such forms. For the avoidance of doubt,where a compound can exist in one of several geometric isomeric ortautomeric forms and only one is specifically described or shown, allothers are nevertheless embraced by formula (I).

For example, in compounds of the formula (I) the pyrazole group may takeeither of the following two tautomeric forms A and B.

For simplicity, the general formula (I) illustrates form A but theformula is to be taken as embracing both form A and form B.

Where compounds of the formula (I) contain one or more chiral centres,and can exist in the form of two or more optical isomers, references tocompounds of the formula (I) include all optical isomeric forms thereof(e.g. enantiomers and diastereoisomers), either as individual opticalisomers, or mixtures or two or more optical isomers, unless the contextrequires otherwise.

For example, the group A can include one or more chiral centres. Thus,when E and R¹ are both attached to the same carbon atom on the linkergroup A, the said carbon atom is typically chiral and hence the compoundof the formula (I) will exist as a pair of enantiomers (or more than onepair of enantiomers where more than one chiral centre is present in thecompound).

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers) or they may be characterised in termsof their absolute stereochemistry using the “R and S” nomenclaturedeveloped by Cahn, Ingold and Prelog, see Advanced Organic Chemistry byJerry March, 4^(th) Edition, John Wiley & Sons, New York, 1992, pages109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed.Engl., 1966, 5, 385-415.

Optical isomers can be separated by a number of techniques includingchiral chromatography (chromatography on a chiral support) and suchtechniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers can beseparated by forming diastereoisomeric salts with chiral acids such as(+)-tartaric acid, (−)-pyroglutamic acid, (−)-di-toluloyl-L-tartaricacid, (+)-mandelic acid, (−)-malic acid, and (−)-camphorsulphonic,separating the diastereoisomers by preferential crystallisation, andthen dissociating the salts to give the individual enantiomer of thefree base.

Where compounds of the formula (I) exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers. Accordingly, the invention providescompositions containing a compound of the formula (I) having one or morechiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%,80%, 85%, 90% or 95%) of the compound of the formula (I) is present as asingle optical isomer (e.g. enantiomer or diastereoisomer). In onegeneral embodiment, 99% or more (e.g. substantially all) of the totalamount of the compound of the formula (I) may be present as a singleoptical isomer (e.g. enantiomer or diastereoisomer).

Esters such as carboxylic acid esters and acyloxy esters of thecompounds of formula (I) bearing a carboxylic acid group or a hydroxylgroup are also embraced by Formula (I). In one embodiment of theinvention, formula (I) includes within its scope esters of compounds ofthe formula (I) bearing a carboxylic acid group or a hydroxyl group. Inanother embodiment of the invention, formula (I) does not include withinits scope esters of compounds of the formula (I) bearing a carboxylicacid group or a hydroxyl group. Examples of esters are compoundscontaining the group —C(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Particular examples of estergroups include, but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃,—C(═O)OC(CH₃)₃, and —C(═O)OPh. Examples of acyloxy (reverse ester)groups are represented by —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Particular examples ofacyloxy groups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Also encompassed by formula (I) are any polymorphic forms of thecompounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexesor clathrates with compounds such as cyclodextrins, or complexes withmetals) of the compounds, and pro-drugs of the compounds. By “prodrugs”is meant for example any compound that is converted in vivo into abiologically active compound of the formula (I).

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is:

C₁₋₇alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C₁₋₇ aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl;

2-(4-morpholino)ethyl); and

acyloxy-C₁₋₇alkyl (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl;

acetoxymethyl; 1-acetoxyethyl;1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl; 1-(benzoyloxy)ethyl;isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl;cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;(4-tetrahydropyranyloxy) carbonyloxymethyl;1-(4-tetrahydropyranyloxy)-carbonyloxyethyl;(4-tetrahydropyranyl)carbonyloxymethyl; and1-(4-tetrahydropyranyl)-carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in antigen-directed enzyme pro-drugtherapy (ADEPT), gene-directed enzyme pro-drug therapy (GDEPT) andligand-directed enzyme pro-drug therapy (LIDEPT). For example, theprodrug may be a sugar derivative or other glycoside conjugate, or maybe an amino acid ester derivative.

Methods for the Preparation of Compounds of the Formula (I)

In this section, as in all other sections of this application, unlessthe context indicates otherwise, references to formula (I) includedreferences to formulae (Ia), (Ib), (II), (III), (IV) and (V) and allother sub-groups, preferences and examples thereof as defined herein.

Compounds of the formula (I) can be prepared by reaction of a compoundof the formula (X) with a compound of the formula (XI) or an N-protectedderivative thereof:

wherein A, E, and R¹ to R⁵ are as hereinbefore defined, one of thegroups X and Y is chlorine, bromine or iodine or atrifluoromethanesulphonate (triflate) group, and the other one of thegroups X and Y is a boronate residue, for example a boronate ester orboronic acid residue.

The reaction can be carried out under typical Suzuki Coupling conditionsin the presence of a palladium catalyst such asbis(tri-t-butylphosphine)palladium and a base (e.g. a carbonate such aspotassium carbonate). The reaction may be carried out in an aqueoussolvent system, for example aqueous ethanol, and the reaction mixture istypically subjected to heating, for example to a temperature in excessof 100° C.

An illustrative synthetic route involving a Suzuki coupling step isshown in Scheme 1. The starting material for the synthetic route shownin scheme 1 is the halo-substituted aryl- or heteroarylmethyl nitrile(XII) in which X is a chlorine, bromine or iodine atom or a triflategroup. The nitrile (XII) is condensed with the aldehyde R¹CHO in thepresence of an alkali such as sodium or potassium hydroxide in anaqueous solvent system such as aqueous ethanol. The reaction can becarried out at room temperature.

The resulting substituted acrylonitrile derivative (XIII) is thentreated with a reducing agent that will selectively reduce the alkenedouble bond without reducing the nitrile group. A borohydride such assodium borohydride may be used for this purpose to give the substitutedacetonitrile derivative (XIV). The reduction reaction is typicallycarried out in a solvent such as ethanol and usually with heating, forexample to a temperature up to about 65° C.

The reduced nitrile (XIV) is then coupled with the pyrazole boronateester (XV) under the Suzuki coupling conditions described above to givea compound of the formula (I) in which A-NR²R³ is a substitutedacetonitrile group.

The substituted acetonitrile compound (XVI) may then be reduced to thecorresponding amine (XVII) by treatment with a suitable reducing agentsuch as Raney nickel and ammonia in ethanol.

The synthetic route shown in Scheme 1 gives rise to amino compounds ofthe formula (I) in which the aryl or heteroaryl group E is attached tothe β-position of the group A relative to the amino group. In order togive amino compounds of the formula (I) in which R¹ is attached to theβ-position relative to the amino group, the functional groups on the twostarting materials in the condensation step can be reversed so that acompound of the formula X-E-CHO wherein X is bromine, chlorine, iodineor a triflate group is condensed with a compound of the formulaR¹—CH₂—CN to give a substituted acrylonitrile derivative which is thenreduced to the corresponding acetonitrile derivative before couplingwith the pyrazole boronate (XV) and reducing the cyano group to an aminogroup.

Compounds of the formula (I) in which R¹ is attached to the α-positionrelative to the amino group can be prepared by the sequence of reactionsshown in Scheme 2.

In Scheme 2, the starting material is a halo-substituted aryl- orheteroarylmethyl Grignard reagent (XVIII, X=bromine or chlorine) whichis reacted with the nitrile R¹—CN in a dry ether such as diethyl etherto give an intermediate imine (not shown) which is reduced to give theamine (XIX) using a reducing agent such as lithium aluminium hydride.The amine (XIX) can be reacted with the boronate ester (XV) under theSuzuki coupling conditions described above to yield the amine (XX).

Compounds of the formula (I) can also be prepared from the substitutednitrile compound (XXI):

wherein PG is a protecting group such as a tetrahydropyranyl group. Thenitrile (XXI) can be condensed with an aldehyde of the formulaR¹—(CH₂)_(r)—CHO, wherein r is 0 or 1, and the resulting substitutedacrylonitrile subsequently reduced to the corresponding substitutednitrile under conditions analogous to those set out in Scheme 1 above.The protecting group PG can then be removed by an appropriate method.The nitrile compound may subsequently be reduced to the correspondingamine by the use of a suitable reducing agent as described above.

The nitrile compound (XXI) may also be reacted with a Grignard reagentof the formula R¹—(CH₂)_(r)—MgBr under standard Grignard reactionconditions followed by deprotection to give an amino compound of theinvention which has the structure shown in formula (XXII).

In the preparative procedures outlined above, the coupling of the arylor heteroaryl group E to the pyrazole is accomplished by reacting ahalo-pyrazole or halo-aryl or heteroaryl compound with a boronate esteror boronic acid in the presence of a palladium catalyst and base. Manyboronates suitable for use in preparing compounds of the invention arecommercially available, for example from Boron Molecular Limited ofNoble Park, Australia, or from Combi-Blocks Inc, of San Diego, USA.Where the boronates are not commercially available, they can be preparedby methods known in the art, for example as described in the reviewarticle by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457. Thus,boronates can be prepared by reacting the corresponding bromo-compoundwith an alkyl lithium such as butyl lithium and then reacting with aborate ester. The resulting boronate ester derivative can, if desired,be hydrolysed to give the corresponding boronic acid.

Compounds of the formula (I) in which the group A contains a nitrogenatom attached to the group E can be prepared by well known syntheticprocedures from compounds of the formula (XXIII) or a protected formthereof. Compounds of the formula (XXIII) can be obtained by a Suzukicoupling reaction of a compound of the formula (XV) (see Scheme 1) witha compound of the formula Br-E-NH₂ such as 4-bromoaniline.

Compounds of the formula (I) in which R¹ and E are connected to the samecarbon atom can be prepared as shown in Scheme 3.

In Scheme 3, an aldehyde compound (XXIV) where X is bromine, chlorine,iodine or a triflate group is condensed with ethyl cyanoacetate in thepresence of a base to give a cyanoacrylate ester intermediate (XXV). Thecondensation is typically carried out in the presence of a base,preferably a non-hydroxide such as piperidine, by heating under DeanStark conditions.

The cyanoacrylate intermediate (XXV) is then reacted with a Grignardreagent R¹MgBr suitable for introducing the group R¹ by Michael additionto the carbon-carbon double bond of the acrylate moiety. The Grignardreaction may be carried out in a polar non-protic solvent such astetrahydrofuran at a low temperature, for example at around 0° C. Theproduct of the Grignard reaction is the cyano propionic acid ester(XXVI) and this is subjected to hydrolysis and decarboxylation to givethe propionic acid derivative (XXVII). The hydrolysis anddecarboxylation steps can be effected by heating in an acidic medium,for example a mixture of sulphuric acid and acetic acid.

The propionic acid derivative (XXVII) is converted to the amide (XXVIII)by reaction with an amine HNR²R³ under conditions suitable for formingan amide bond. The coupling reaction between the propionic acidderivative (XXVII) and the amine HNR²R³ is preferably carried out in thepresence of a reagent of the type commonly used in the formation ofpeptide linkages. Examples of such reagents include1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J. Amer. Chem Soc.1955, 77, 1067), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide(referred to herein either as EDC or EDAC) (Sheehan et al, J. Org.Chem., 1961, 26, 2525), uronium-based coupling agents such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and phosphonium-based coupling agents such as1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205).Carbodiimide-based coupling agents are advantageously used incombination with 1-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, J.Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt)(Konig et al, Chem. Ber., 103, 708, 2024-2034). Preferred couplingreagents include EDC (EDAC) and DCC m combination with HOAt or HOBt.

The coupling reaction is typically carried out in a non-aqueous,non-protic solvent such as acetonitrile, dioxan, dimethylsulphoxide,dichloromethane, dimethylformamide or N-methylpyrrolidine, or in anaqueous solvent optionally together with one or more miscibleco-solvents. The reaction can be carried out at room temperature or,where the reactants are less reactive (for example in the case ofelectron-poor anilines bearing electron withdrawing groups such assulphonamide groups) at an appropriately elevated temperature. Thereaction may be carried out in the presence of a non-interfering base,for example a tertiary amine such as triethylamine orN,N-diisopropylethylamine.

Where the amine HNR²R³ is ammonia, the amide coupling reaction can becarried out using 1,1′-carbonyldiimidazole (CDI) to activate thecarboxylic acid before addition of the ammonia.

As an alternative, a reactive derivative of the carboxylic acid, e.g. ananhydride or acid chloride, may be used. Reaction with a reactivederivative such an anhydride is typically accomplished by stirring theamine and anhydride at room temperature in the presence of a base suchas pyridine.

The amide (XXVIII) can be converted to a compound of the formula (XXX)(which corresponds to a compound of the formula (I) wherein A has an oxosubstituent next to the NR²R³ group) by reaction with a boronate (XV)under Suzuki coupling conditions as described above. The amide (XXX) cansubsequently be reduced using a hydride reducing agent such as lithiumaluminium hydride in the presence of aluminium chloride to give an amineof the formula (XXXI) (which corresponds to a compound of the formula(I) wherein A is CH—CH₂—CH₂—). The reduction reaction is typicallycarried out in an ether solvent, for example diethyl ether, with heatingto the reflux temperature of the solvent.

Rather than reacting the amide (XXVIII) with the boronate (XV), theamide may instead be reduced with lithium aluminium hydride/aluminiumchloride, for example in an ether solvent at ambient temperature, togive the amine (XXIX) which is then reacted with the boronate (XV) underthe Suzuki coupling conditions described above to give the amine (XXX).

In order to obtain the homologue of the amine (XXIX) containing onefewer methylene group, the carboxylic acid (XXVII) can be converted tothe azide by standard methods and subjected to a Curtius rearrangementin the presence of an alcohol such as benzyl alcohol to give a carbamate(see Advanced Organic Chemistry, 4^(th) edition, by Jerry March, JohnWiley & sons, 1992, pages 1091-1092). The benzylcarbamate can functionas a protecting group for the amine during the subsequent Suzukicoupling step, and the benzyloxycarbonyl moiety in the carbamate groupcan then be removed by standard methods after the coupling step.Alternatively, the benzylcarbamate group can be treated with a hydridereducing agent such as lithium aluminium hydride to give a compound inwhich NR²R³ is a methylamino group instead of an amino group.

Intermediate compounds of the formula (X) where the moiety X is achlorine, bromine or iodine atom and A is a group CH—CH₂— can beprepared by the reductive amination of an aldehyde compound of theformula (XXXII):

with an amine of the formula HNR²R³ under standard reductive aminationconditions, for example in the presence of sodium cyanoborohydride in analcohol solvent such as methanol or ethanol.

The aldehyde compound (XXXII) can be obtained by oxidation of thecorresponding alcohol (XXXIII) using, for example, the Dess-Martinperiodinane (see Dess, D. B.; Martin, J. C. J. Org. Soc., 1983, 48, 4155and Organic Syntheses, Vol. 77, 141).

Compounds of the formula (I) where A, N and R² together form a cyclicgroup can be formed by the Suzuki coupling of a boronate compound of theformula (XV) with a cyclic intermediate of the formula (XXXIV) or anN-protected derivative thereof.

Cyclic intermediates of the formula (XXXIV), where R¹ is an aryl groupsuch as an optionally substituted phenyl group, can be formed by FriedelCrafts alkylation of an aryl compound R¹—H with a compound of theformula (XXXV):

The alkylation is typically carried out in the presence of a Lewis acidsuch as aluminium chloride at a reduced temperature, for example lessthan 5° C.

The Friedel Crafts reaction has been found to be of generalapplicability to the preparation of a range of intermediates of theformula (X). Accordingly, in a general method of making compounds of theformula (X), a compound of the formula (LXX):

is reacted with a compound of the formula R¹—H under Friedel Craftsalkylation conditions, for example in the presence of an aluminium,halide (e.g. AlCl₃).

In a further method for the preparation of a compound of the formula (I)wherein the moiety NR²R³ is attached to a CH₂ group of the moiety A, analdehyde of the formula (XXXVI) can be coupled with an amine of theformula HNR²R³ under reductive amination conditions as described above.In the formulae (XXXVI) and (XXXVII), A′ is the residue of the groupA—i.e. the moieties A′ and CH₂ together form the group A. The aldehyde(XXXVII) can be formed by oxidation of the corresponding alcohol using,for example, Dess-Martin periodinane.

A Friedel Crafts alkylation procedure of the type described above forthe synthesis of intermediates of the formula (XXXIV) can also be usedto prepare intermediates of the formula (X) wherein X is bromine. Anexample of such a procedure is shown in Scheme 4.

The starting material for the synthetic route shown in Scheme 4 is theepoxide (XXXVIII) which can either be obtained commercially or can bemade by methods well known to the skilled person, for example byreaction of the aldehyde Br-E-CHO with trimethylsulphonium iodide. Theepoxide (XXXVIII) is reacted with an amine HNR²R³ under conditionssuitable for a ring-opening reaction with the epoxide to give a compoundof the formula (XXXIX). The ring opening reaction can be carried out ina polar solvent such as ethanol at room temperature or optionally withmild heating, and typically with a large excess of the amine.

The amine (XXXIX) is then reacted with an aryl compound R¹H, typically aphenyl compound, capable of taking part in a Friedel Crafts alkylation(see for example Advanced Organic Chemistry, by Jerry March, pages534-542). Thus, the amine of formula (XXXIX) is typically reacted withthe aryl compound R¹H in the presence of an aluminium chloride catalystat or around room temperature. Where the aryl compound R¹H is a liquid,e.g. as in the case of a methoxybenzene (e.g. anisole) or a halobenzenesuch as chlorobenzene, the aryl compound may serve as the solvent.Otherwise, a less reactive solvent such as nitrobenzene may be used. TheFriedel Crafts alkylation of the compound R¹H with the amine (XXXIX)gives a compound of the formula (XL) which corresponds to a compound ofthe formula (X) wherein X is bromine and A is CHCH₂.

The hydroxy intermediate (XXXIX) in Scheme 4 can also be used to preparecompounds of the formula (X) in which the carbon atom of the hydrocarbonlinker group A adjacent the group R¹ is replaced by an oxygen atom. Thusthe compound of formula (XXXIX), or an N-protected derivative thereof(where R² or R³ are hydrogen) can be reacted with a phenolic compound ofthe formula R¹—OH under Mitsunobu alkylation conditions, e.g. in thepresence of diethyl azodicarboxylate and triphenylphosphine. Thereaction is typically carried out in a polar non-protic solvent such astetrahydrofuran at a moderate temperature such as ambient temperature.

A further use of the hydroxy-intermediate (XXXIX) is for the preparationof the corresponding fluoro-compound. Thus, the hydroxy group can bereplaced by fluorine by reaction with pyridine:hydrogen fluoride complex(Olah's reagent). The fluorinated intermediate can then be subjected toa Suzuki coupling reaction to give a compound of the formula (I) with afluorinated hydrocarbon group A. A fluorinated compound of the formula(I) could alternatively be prepared by first coupling the hydroxyintermediate (XXXIX), or a protected form thereof, with a pyrazoleboronic acid or boronate under Suzuki conditions and then replacing thehydroxy group in the resulting compound of formula (I) with fluorineusing pyridine: hydrogen fluoride complex.

Compounds of the formula (I) in which the moiety:

is a group:

where A″ is the hydrocarbon residue of the group A, can be prepared bythe sequence of reactions shown in Scheme 5.

As shown in Scheme 5, the aldehyde (XXIV) is reacted with a Grignardreagent R¹MgBr under standard Grignard conditions to give the secondaryalcohol (XLI). The secondary alcohol can then be reacted with a compoundof the formula (XLII) in which R^(2′) and R^(3′) represent the groups R²and R³ or an amine-protecting group, A″ is the residue of the group A,and X′ represents a hydroxy group or a leaving group.

The amine protecting group can be, for example, a phthalolyl group inwhich case NR^(2′)R^(3′) is a phthalimido group.

When X¹ is a hydroxy group, the reaction between compound (XLI) and(XLII) can take the form of an toluene sulphonic acid catalysedcondensation reaction. Alternatively, when X′ is a leaving group such ashalogen, the alcohol (XLI) can first be treated with a strong base suchas sodium hydride to form the alcoholate which then reacts with thecompound (XLII).

The resulting compound of the formula (XLIII) is then subjected to aSuzuki coupling reaction with the pyrazole boronate reagent (XV) undertypical Suzuki coupling conditions of the type described above to give acompound of the formula (XLIV). The protecting group can then be removedfrom the protected amine group NR^(2′)R^(3′) to give a compound of theformula (I).

Compounds of the formula (I) in which the moiety:

is a group:

where A″ is the hydrocarbon residue of the group A, can be prepared bythe sequence of reactions shown in Scheme 6.

The starting material in Scheme 6 is the chloroacyl compound (XLV) whichcan be prepared by literature methods (e.g. the method described in J.Med. Chem., 2004, 47, 3924-3926) or methods analogous thereto. Compound(XLV) is converted into the secondary alcohol (XLVI) by reduction with ahydride reducing agent such as sodium borohydride in a polar solventsuch as water/tetrahydrofuran.

The secondary alcohol (XLVI) can then be reacted with a phenoliccompound of the formula R¹—OH under Mitsunobu alkylation conditions,e.g. in the presence of diethyl azodicarboxylate and triphenylphosphine,as described above, to give the aryl ether compound (XLVII).

The chorine atom in the aryl ether compound (XLVII) is then displaced byreaction with an amine HNR²R³ to give a compound of the formula(XLVIII). The nucleophilic displacement reaction may be carried out byheating the amine with the aryl ether in a polar solvent such as analcohol at an elevated temperature, for example approximately 100° C.The heating may advantageously be achieved using a microwave heater. Theresulting amine (XLVIII) can then be subjected to a Suzuki couplingprocedure with a boronate of the formula (XV) as described above to givethe compound (XLIX).

In a variation on the reaction sequence shown in Scheme 6, the secondaryalcohol (XLVI) can be subjected to a nucleophilic displacement reactionwith an amine HNR²R³ before introducing the group R¹ by means of theMitsunobu ether-forming reaction.

Another route to compounds of the formula (I) in which E and R¹ areattached to the same carbon atom in the group A is illustrated in Scheme7.

In Scheme 7, an N-protected pyrazolyl boronic acid (L) is reacted underSuzuki coupling conditions with the cyano compound X-E-CN in which X istypically a halogen such as bromine or chlorine. The protecting group PGat the 1-position of the pyrazole ring may be, for example, atriphenylmethyl (trityl) group. The boronic acid (L) can be preparedusing the method described in EP 1382603 or methods analogous thereto.

The resulting nitrile (LI) may then be reacted with a Grignard reagentR¹—MgBr to introduce the group R¹ and form the ketone (LII). The ketone(LII) is converted to the enamine (LIV) by reaction with thediphenylphosphinoylmethylamine (LIII) in the presence of a strong basesuch as an alkyl lithium, particularly butyl lithium.

The enamine (LIV) is then subjected to hydrogenation over a palladium oncharcoal catalyst to reduce the double bond of the enamine and removethe 1-phenethyl group. Where the protecting group PG is a trityl group,hydrogenation also removes the trityl group, thereby yielding a compoundof the formula (LV).

Alternatively, the enamine (LIV) can be reduced with a hydride reducingagent under the conditions described in Tetrahedron: Asymmetry 14 (2003)1309-1316 and subjected to a chiral separation. Removal of theprotecting 2-phenethyl group and the protecting group PG then gives anoptically active form of the compound of formula (LV).

Intermediates of the formula (X) wherein A and R² link to form a ringcontaining an oxygen atom can be prepared by the general methodillustrated in Scheme 8.

In Scheme 8, a ketone (LVI) is reacted with trimethylsulphonium iodideto form the epoxide (LVII). The reaction is typically carried out in thepresence of a hydride base such as sodium hydride in a polar solventsuch as dimethylsulphoxide.

The epoxide (LVII) is subjected to a ring opening reaction withethanolamine in the presence of a non-interfering base such astriethylamine in a polar solvent such as an alcohol (e.g. isopropanol),usually with mild heating (e.g. up to approximately 50° C. The resultingsecondary alcohol is then cyclised to form the morpholine ring bytreatment with concentrated sulphuric acid in a solvent such asethanolic dichloromethane.

The morpholine intermediate (LIX) can then reacted with the boronate(XV) under Suzuki coupling conditions to give the compound of formula(LX), which corresponds to a compound of the formula (I) in whichA-NR²R³ forms a morpholine group.

Instead of reacting the epoxide (LVII) with ethanolamine, it may insteadbe reacted with mono- or dialkylamines thereby providing a route tocompounds containing the moiety:

Compounds wherein R² and R³ are both hydrogen can be prepared byreacting the epoxide (LVII) with potassium phthalimide in a polarsolvent such as DMSO. During the Suzuki coupling step, the phthalimidegroup may undergo partial hydrolysis to give the correspondingphthalamic acid which can be cleaved using hydrazine to give the aminogroup NH₂. Alternatively, the phthalamic acid can be recyclised to thephthalimide using a standard amide-forming reagent and the phthaloylgroup then removed using hydrazine to give the amine.

A further synthetic route to compounds of the formula (I) wherein A andNR²R³ combine to form a cyclic group is illustrated in Scheme 9.

In Scheme 9, the starting material (LXI) is typically adi-aryl/heteroaryl methane in which one or both of the aryl/heteroarylgroups is capable of stabilising or facilitating formation of an anionformed on the methylene group between E and R¹. For example, R¹ mayadvantageously be a pyridine group. The starting material (LXI) isreacted with the N-protected bis-2-chloroethylamine (LXII) in thepresence of a non-interfering strong base such as sodiumhexamethyldisilazide in a polar solvent such as tetrahydrofuran at areduced temperature (e.g. around 0° C.) to give the N-protected cyclicintermediate (LXIII). The protecting group can be any standardamine-protecting group such as a Boc group. Following cyclisation, theintermediate (LXIII) is coupled to a boronate of the formula (XV) underSuzuki coupling conditions and then deprotected to give the compound ofthe formula (I).

Compounds of the formula (I) in which the moiety:

is a group:

wherein “Alk” is a small alkyl group such as methyl or ethyl can beformed by the synthetic route illustrated in Scheme 10.

In Scheme 10, a carboxylic acid of the formula (LXIV) is esterified bytreatment with methanol in the presence of an acid catalyst such ashydrochloric acid. The ester (LXV) is then reacted with a strong basesuch as lithium diisopropylamide (LDA) and an alkyl iodide such asmethyl iodide at reduced temperature (e.g. between 0° C. and −78° C.).The branched ester (LXVI) is then hydrolysed to the acid (LXVII) andcoupled with an amine HNR²R³ under standard amide forming conditions ofthe type described above. The amide (LXVIII) can then be reduced to theamine (LXIX) using lithium aluminium hydride, and the amine (LXIX) isthen reacted with a pyrazole boronate or boronic acid under Suzukicoupling conditions to give a compound of the formula (I).

Once formed, many compounds of the formula (I) can be converted intoother compounds of the formula (I) using standard functional groupinterconversions. For example, compounds of the formula (I) in which theNR²R³ forms part of a nitrile group can be reduced to the correspondingamine. Compounds in which NR²R³ is an NH₂ group can be converted to thecorresponding alkylamine by reductive alkylation, or to a cyclic group.Compounds wherein R¹ contains a halogen atom such as chlorine or brominecan be used to introduce an aryl or heteroaryl group substituent intothe R¹ group by means of a Suzuki coupling reaction. Further examples ofinterconversions of one compound of the formula (I) to another compoundof the formula (I) can be found in the examples below. Additionalexamples of functional group interconversions and reagents andconditions for carrying out such conversions can be found in, forexample, Advanced Organic Chemistry, by Jerry March, 4^(th) edition,119, Wiley Interscience, New York, Fiesers' Reagents for OrganicSynthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN.0-471-58283-2), and Organic Syntheses, Volumes 1-8, John Wiley, editedby Jeremiah P. Freeman (ISBN: 0-471-31192-8).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

A hydroxy group may be protected, for example, as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc). Analdehyde or ketone group may be protected, for example, as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid. An amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), or as a2-(phenylsulphonyl)ethyloxy amide (—NH-Psec). Other protecting groupsfor amines, such as cyclic amines and heterocyclic N—H groups, includetoluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups and benzylgroups such as a para-methoxybenzyl (PMB) group. A carboxylic acid groupmay be protected as an ester for example, as: an C₁₋₇ alkyl ester (e.g.,a methyl ester; a t-butyl ester); a C₁₋₇ haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); a triC₁₋₇ alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇ alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or asan amide, for example, as a methyl amide. A thiol group may beprotected, for example, as a thioether (—SR), for example, as: a benzylthioether; an acetamidomethyl ether (—S—CH₂NHC(═O)CH₃).

The 1(H) position of the pyrazole group in the compounds of the formula(I) or its precursors can be protected by a variety of groups, theprotecting group being selected according to the nature of the reactionconditions to which the group is exposed. Examples of protecting groupsfor the pyrazole N—H include tetrahydropyranyl, benzyl and4-methoxybenzyl groups.

Many of the chemical intermediates described above are novel and suchnovel intermediates form a further aspect of the invention.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation) comprising at least one active compound of the inventiontogether with one or more pharmaceutically acceptable carriers,adjuvants, excipients, diluents, fillers, buffers, stabilisers,preservatives, lubricants, or other materials well known to thoseskilled in the art and optionally other therapeutic or prophylacticagents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one active compound, as definedabove, together with one or more pharmaceutically acceptable carriers,excipients, buffers, adjuvants, stabilizers, or other materials, asdescribed herein.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g. human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

Accordingly, in a further aspect, the invention provides compounds ofthe formula (I) and sub-groups thereof as defined herein in the form ofpharmaceutical compositions.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, ophthalmic, otic, rectal,intra-vaginal, or transdermal administration. Where the compositions areintended for parenteral administration, they can be formulated forintravenous, intramuscular, intraperitoneal, subcutaneous administrationor for direct delivery into a target organ or tissue by injection,infusion or other means of delivery.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets.

In one preferred embodiment of the invention, the pharmaceuticalcomposition is in a form suitable for i.v. administration, for exampleby injection or infusion.

In another preferred embodiment, the pharmaceutical composition is in aform suitable for sub-cutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration includetablets, capsules, caplets, pills, lozenges, syrups, solutions, powders,granules, elixirs and suspensions, sublingual tablets, wafers or patchesand buccal patches.

Pharmaceutical compositions containing compounds of the formula (I) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

Thus, tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, e.g. lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starchessuch as corn starch. Tablets may also contain such standard ingredientsas binding and granulating agents such as polyvinylpyrrolidone,disintegrants (e.g. swellable crosslinked polymers such as crosslinkedcarboxymethylcellulose), lubricating agents (e.g. stearates),preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents(for example phosphate or citrate buffers), and effervescent agents suchas citrate/bicarbonate mixtures. Such excipients are well known and donot need to be discussed in detail here.

Capsule formulations may be of the hard gelatin or soft gelatin varietyand can contain the active component in solid, semi-solid, or liquidform. Gelatin capsules can be formed from animal gelatin or synthetic orplant derived equivalents thereof.

The solid dosage forms (e.g. tablets, capsules etc.) can be coated orun-coated, but typically have a coating, for example a protective filmcoating (e.g. a wax or varnish) or a release controlling coating. Thecoating (e.g. a Eudragit™ type polymer) can be designed to release theactive component at a desired location within the gastro-intestinaltract. Thus, the coating can be selected so as to degrade under certainpH conditions within the gastrointestinal tract, thereby selectivelyrelease the compound in the stomach or in the ileum or duodenum.

Instead of, or in addition to, a coating, the drug can be presented in asolid matrix comprising a release controlling agent, for example arelease delaying agent which may be adapted to selectively release thecompound under conditions of varying acidity or alkalinity in thegastrointestinal tract. Alternatively, the matrix material or releaseretarding coating can take the form of an erodible polymer (e.g. amaleic anhydride polymer) which is substantially continuously eroded asthe dosage form passes through the gastrointestinal tract. As a furtheralternative, the active compound can be formulated in a delivery systemthat provides osmotic control of the release of the compound. Osmoticrelease and other delayed release or sustained release formulations maybe prepared in accordance with methods well known to those skilled inthe art.

Compositions for topical use include ointments, creams, sprays, patches,gels, liquid drops and inserts (for example intraocular inserts). Suchcompositions can be formulated in accordance with known methods.

Compositions for parenteral administration are typically presented assterile aqueous or oily solutions or fine suspensions, or may beprovided in finely divided sterile powder form for making upextemporaneously with sterile water for injection.

Examples of formulations for rectal or intra-vaginal administrationinclude pessaries and suppositories which may be, for example, formedfrom a shaped moldable or waxy material containing the active compound.

Compositions for administration by inhalation may take the form ofinhalable powder compositions or liquid or powder sprays, and can beadministrated in standard form using powder inhaler devices or aerosoldispensing devices. Such devices are well known. For administration byinhalation, the powdered formulations typically comprise the activecompound together with an inert solid powdered diluent such as lactose.

The compounds of the inventions will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation intended for oral administration may contain from 1 nanogramto 2 milligrams, for example 0.1 milligrams to 2 grams of activeingredient, more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams, or 0.1 milligrams to 2 milligrams.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect.

Protein Kinase Inhibitory Activity

The activity of the compounds of the invention as inhibitors of proteinkinase A and protein kinase B can be measured using the assays set forthin the examples below and the level of activity exhibited by a givencompound can be defined in terms of the IC50 value. Preferred compoundsof the present invention are compounds having an IC₅₀ value of less than1 μM, more preferably less than 0.1 μM, against protein kinase B.

Therapeutic Uses

Prevention or Treatment of Proliferative Disorders

The compounds of the formula (I) are inhibitors of protein kinase A andprotein kinase B. As such, they are expected to be useful in providing ameans of preventing the growth of or inducing apoptosis of neoplasias.It is therefore anticipated that the compounds will prove useful intreating or preventing proliferative disorders such as cancers. Inparticular tumours with deletions or inactivating mutations in PTEN orloss of PTEN expression or rearrangements in the (T-cell lytmphocyte)TCL-1 gene may be particularly sensitive to PKB inhibitors. Tumourswhich have other abnormalities leading to an upregulated PKB pathwaysignal may also be particularly sensitive to inhibitors of PKB. Examplesof such abnormalities include but are not limited to overexpression ofone or more PI3K subunits, over-expression of one or more PKB isoforms,or mutations in PI3K, PDK1, or PKB which lead to an increase in thebasal activity of the enzyme in question, or upregulation oroverexpression or mutational activation of a growth factor receptor suchas a growth factor selected from the epidermal growth factor receptor(EGFR), fibroblast growth factor receptor (FGFR), platelet derivedgrowth factor receptor (PDGFR), insulin-like growth factor 1 receptor(IGF-1R) and vascular endothelial growth factor receptor (VEGFR)families.

It is also envisaged that the compounds of the invention will be usefulin treating other conditions which result from disorders inproliferation or survival such as viral infections, andneurodegenerative diseases for example. PKB plays an important role inmaintaining the survival of immune cells during an immune response andtherefore PKB inhibitors could be particularly beneficial in immunedisorders including autoimmune conditions.

Therefore, PKB inhibitors could be useful in the treatment of diseasesin which there is a disorder of proliferation, apoptosis ordifferentiation.

PKB inhibitors may also be useful in diseases resulting from insulinresistance and insensitivity, and the disruption of glucose, energy andfat storage such as metabolic disease and obesity.

Examples of cancers which may be inhibited include, but are not limitedto, a carcinoma, for example a carcinoma of the bladder, breast, colon(e.g. colorectal carcinomas such as colon adenocarcinoma and colonadenoma), kidney, epidermal, liver, lung, for example adenocarcinoma,small cell lung cancer and non-small cell lung carcinomas, oesophagus,gall bladder, ovary, pancreas e.g. exocrine pancreatic carcinoma,stomach, cervix, endometrium, thyroid, prostate, or skin, for examplesquamous cell carcinoma; a hematopoietic tumour of lymphoid lineage, forexample leukaemia, acute lymphocytic leukaemia, B-cell lymphoma, T-celllymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloidlineage, for example acute and chronic myelogenous leukaemias,myelodysplastic syndrome, or promyelocytic leukaemia; thyroid follicularcancer; a tumour of mesenchymal origin, for example fibro sarcoma orhabdomyosarcoma; a tumour of the central or peripheral nervous system,for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma;seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentosum;keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth, the disease or condition comprising abnormal cell growth in oneembodiment is a cancer.

Particular subsets of cancers include breast cancer, ovarian cancer,colon cancer, prostate cancer, oesophageal cancer, squamous cancer andnon-small cell lung carcinomas.

A further subset of cancers includes breast cancer, ovarian cancer,prostate cancer, endometrial cancer and glioma.

It is also possible that some protein kinase B inhibitors can be used incombination with other anticancer agents. For example, it may bebeneficial to combine of an inhibitor that induces apoptosis withanother agent which acts via a different mechanism to regulate cellgrowth thus treating two of the characteristic features of cancerdevelopment. Examples of such combinations are set out below.

Immune Disorders

Immune disorders for which PKA and PKB inhibitors may be beneficialinclude but are not limited to autoimmune conditions and chronicinflammatory diseases, for example systemic lupus erythematosus,autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus, Eczemahypersensitivity reactions, asthma, COPD, rhinitis, and upperrespiratory tract disease.

Other Therapeutic Uses

PKB plays a role in apoptosis, proliferation, differentiation andtherefore PKB inhibitors could also be useful in the treatment of thefollowing diseases other than cancer and those associated with immunedysfunction; viral infections, for example herpes virus, pox virus,Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV;prevention of AIDS development in HIV-infected individuals;cardiovascular diseases for example cardiac hypertrophy, restenosis,atherosclerosis; neurodegenerative disorders, for example Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotropic lateralsclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellardegeneration; glomerulonephritis; myelodysplastic syndromes, ischemicinjury associated myocardial infarctions, stroke and reperfusion injury,degenerative diseases of the musculoskeletal system, for example,osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cysticfibrosis, multiple sclerosis, kidney diseases.

Methods of Treatment

It is envisaged that the compounds of the formula (I) will useful in theprophylaxis or treatment of a range of disease states or conditionsmediated by protein kinase A and/or protein kinase B. Examples of suchdisease states and conditions are set out above.

Compounds of the formula (I) are generally administered to a subject inneed of such administration, for example a human or animal patient,preferably a human.

The compounds will typically be administered in amounts that aretherapeutically or prophylactically useful and which generally arenon-toxic. However, in certain situations (for example in the case oflife threatening diseases), the benefits of administering a compound ofthe formula (I) may outweigh the disadvantages of any toxic effects orside effects, in which case it may be considered desirable to administercompounds in amounts that are associated with a degree of toxicity.

The compounds may be administered over a prolonged term to maintainbeneficial therapeutic effects or may be administered for a short periodonly. Alternatively they may be administered in a pulsatile manner.

A typical daily dose of the compound can be in the range from 100picograms to 100 milligrams per kilogram of body weight, typically 10nanograms to 10 milligrams per kilogram of bodyweight, more typically 1microgram to 10 milligrams although higher or lower doses may beadministered where required. Ultimately, the quantity of compoundadministered will be commensurate with the nature of the disease orphysiological condition being treated and will be at the discretion ofthe physician.

The compounds of the formula (I) can be administered as the soletherapeutic agent or they can be administered in combination therapywith one of more other compounds for treatment of a particular diseasestate, for example a neoplastic disease such as a cancer as hereinbeforedefined. Examples of other therapeutic agents or treatments that may beadministered together (whether concurrently or at different timeintervals) with the compounds of the formula (I) include but are notlimited to:

-   -   Topoisomerase I inhibitors    -   Antimetabolites    -   Tubulin targeting agents    -   DNA binder and topoisomerase II inhibitors    -   Alkylating Agents    -   Monoclonal Antibodies.    -   Anti-Hormones    -   Signal Transduction Inhibitors    -   Proteasome Inhibitors    -   DNA methyl transferases    -   Cytokines and retinoids    -   Radiotherapy.

For the case of protein kinase A inhibitors or protein kinase Binhibitors combined with other therapies the two or more treatments maybe given in individually varying dose schedules and via differentroutes.

Where the compound of the formula (I) is administered in combinationtherapy with one or more other therapeutic agents, the compounds can beadministered simultaneously or sequentially. When administeredsequentially, they can be administered at closely spaced intervals (forexample over a period of 5-10 minutes) or at longer intervals (forexample 1, 2, 3, 4 or more hours apart, or even longer periods apartwhere required), the precise dosage regimen being commensurate with theproperties of the therapeutic agent(s).

The compounds of the invention may also be administered in conjunctionwith non-chemotherapeutic treatments such as radiotherapy, photodynamictherapy, gene therapy; surgery and controlled diets.

For use in combination therapy with another chemotherapeutic agent, thecompound of the formula (I) and one, two, three, four or more othertherapeutic agents can be, for example, formulated together in a dosageform containing two, three, four or more therapeutic agents. In analternative, the individual therapeutic agents may be formulatedseparately and presented together in the form of a kit, optionally withinstructions for their use.

A person skilled in the art would know through their common generalknowledge the dosing regimes and combination therapies to use.

Methods of Diagnosis

Prior to administration of a compound of the formula (I), a patient maybe screened to determine whether a disease or condition from which thepatient is or may be suffering is one which would be susceptible totreatment with a compound having activity against protein kinase Aand/or protein kinase B.

For example, a biological sample taken from a patient may be analysed todetermine whether a condition or disease, such as cancer, that thepatient is or may be suffering from is one which is characterised by agenetic abnormality or abnormal protein expression which leads toup-regulation of PKA and/or PKB or to sensitisation of a pathway tonormal PKA and/or PKB activity, or to upregulation of a signaltransduction component upstream of PKA and/or PKB such as, in the caseof PKB, P13K, GF receptor and PDK 1 & 2.

Alternatively, a biological sample taken from a patient may be analysedfor loss of a negative regulator or suppressor of the PKB pathway suchas PTEN. In the present context, the term “loss” embraces the deletionof a gene encoding the regulator or suppressor, the truncation of thegene (for example by mutation), the truncation of the transcribedproduct of the gene, or the inactivation of the transcribed product(e.g. by point mutation) or sequestration by another gene product.

The term up-regulation includes elevated expression or over-expression,including gene amplification (i.e. multiple gene copies) and increasedexpression by a transcriptional effect, and hyperactivity andactivation, including activation by mutations. Thus, the patient may besubjected to a diagnostic test to detect a marker characteristic ofup-regulation of PKA and/or PKB. The term diagnosis includes screening.By marker we include genetic markers including, for example, themeasurement of DNA composition to identify mutations of PKA and/or PKB.The term marker also includes markers which are characteristic of upregulation of PKA and/or PKB, including enzyme activity, enzyme levels,enzyme state (e.g. phosphorylated or not) and mRNA levels of theaforementioned proteins.

The above diagnostic tests and screens are typically conducted on abiological sample selected from tumour biopsy samples, blood samples(isolation and enrichment of shed tumour cells), stool biopsies, sputum,chromosome analysis, pleural fluid, peritoneal fluid, or urine.

Identification of an individual carrying a mutation in PKA and/or PKB ora rearrangement of TCL-1 or loss of PTEN expression may mean that thepatient would be particularly suitable for treatment with a PKA and/orPKB inhibitor. Tumours may preferentially be screened for presence of aPKA and/or PKB variant prior to treatment. The screening process willtypically involve direct sequencing, oligonucleotide microarrayanalysis, or a mutant specific antibody.

Methods of identification and analysis of mutations and up-regulation ofproteins are known to a person skilled in the art. Screening methodscould include, but are not limited to, standard methods such asreverse-transcriptase polymerase chain reaction (RT-PCR) or in-situhybridisation.

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR.

Methods of PCR amplification, the selection of primers, and conditionsfor amplification, are known to a person skilled in the art. Nucleicacid manipulations and PCR are carried out by standard methods, asdescribed for example in Ausubel, F. M. et al., eds. Current Protocolsin Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M. A.et-al., eds. PCR Protocols: a guide to methods and applications, 1990,Academic Press, San Diego. Reactions and manipulations involving nucleicacid techniques are also described in Sambrook et al., 2001, 3^(rd) Ed,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor LaboratoryPress. Alternatively a commercially available kit for RT-PCR (forexample Roche Molecular Biochemicals) may be used, or methodology as setforth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659,5,272,057, 5,882,864, and 6,218,529 and incorporated herein byreference.

An example of an in-situ hybridisation technique for assessing mRNAexpression would be fluorescence in-situ hybridisation (FISH) (seeAngerer, 1987 Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labeled,for example, with radioisotopes or fluorescent reporters. Preferredprobes are sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. Current Protocols in Molecular Biology,2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed., ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Alternatively, the protein products expressed from the mRNAs may beassayed by immunohistochemistry of tumour samples, solid phaseimmunoassay with microtitre plates, Western blotting, 2-dimensionalSDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and othermethods known in the art for detection of specific proteins. Detectionmethods would include the use of site specific antibodies. The skilledperson will recognize that all such well-known techniques for detectionof upregulation of PKB, or detection of PKB variants could be applicablein the present case.

Therefore all of these techniques could also be used to identify tumoursparticularly suitable for treatment with PKA and/or PKB inhibitors.

For example, as stated above, PKB beta has been found to be upregulatedin 10-40% of ovarian and pancreatic cancers (Bellacosa et al 1995, Int.J. Cancer 64, 280-285; Cheng et al 1996, PNAS 93, 3636-3641; Yuan et al2000, Oncogene 19, 2324-2330). Therefore it is envisaged that PKBinhibitors, and in particular inhibitors of PKB beta, may be used totreat ovarian and pancreatic cancers.

PKB alpha is amplified in human gastric, prostate and breast cancer(Staal 1987, PNAS 84, 5034-5037; Sun et al 2001, Am. J. Pathol. 159,431-437). Therefore it is envisaged that PKB inhibitors, and inparticular inhibitors of PKB alpha, may be used to treat human gastric,prostate and breast cancer.

Increased PKB gamma activity has been observed in steroid independentbreast and prostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274,21528-21532). Therefore it is envisaged that PKB inhibitors, and inparticular inhibitors of PKB gamma, may be used to treat steroidindependent breast and prostate cancers.

EXPERIMENTAL

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following procedures andexamples.

The starting materials for each of the procedures described below arecommercially available unless otherwise specified.

In the examples, the compounds prepared were characterised by liquidchromatography, mass spectroscopy and 1H nuclear magnetic resonancespectroscopy using the systems and operating conditions set out below.

Proton magnetic resonance (¹H NMR) spectra were recorded on a BrukerAV400 instrument operating at 400.13 MHz, in Me-d₃-OD at 27 C, unlessotherwise stated and are reported as follows: chemical shift δ/ppm(number of protons, multiplicity where s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet, br=broad). The residual protic solvent MeOH(δ_(H)=3.31 ppm) was used as the internal reference.

For the mass spectra, where chlorine is present, the mass quoted for thecompound is for ³⁵Cl.

In each of the examples, where the compounds are isolated or formed asthe free base, they can be converted into a salt form such as an aceticacid or hydrochloric acid salt. Conversely, where the compounds areisolated or formed as a salt, the salt can be converted into thecorresponding free base by methods well known to the skilled person, andthen optionally converted to another salt.

A number of liquid chromatography systems were used and these aredescribed below.

Platform System

HPLC System: Waters 2795

Mass Spec Detector: Micromass Platform LC

PDA Detector: Waters 2996 PDA

Acidic Analytical Conditions 1:

Eluent A: H₂O (0.1% Formic Acid)

Eluent B: CH₃CN (0.1% Formic Acid)

Gradient: 5-95% eluent B over 3.5 minutes

Flow: 1.5 ml/min

Column: Phenomenex Synergi 4μ Max-RP 80A, 50×4.6 mm

Acidic Analytical Conditions 2:

Eluent A. H₂O (0.1% Formic Acid)

Eluent B: CH₃CN (0.1% Formic Acid)

Gradient: 5-95% eluent B over 3.5 minutes

Flow: 0.8 ml/min

Column: Phenomenex Synergi 4μ Max-RP 80A, 50×2.0 mm

Acidic Analytical Conditions 3:

Eluent A: H₂O (0.1% Formic Acid)

Eluent B: CH₃CN (0.1% Formic Acid)

Gradient: 5-95% eluent B over 15 minutes

Flow: 0.4 ml/mm

Column: Phenomenex Synergi 4μ Max-RP 80A, 50×2.0 mm

Basic Analytical Conditions 1:

Eluent A: H₂O (10 mM NH₄HCO₃ buffer adjusted to pH=9.5 with NH₄OH)

Eluent B: CH₃CN

Gradient: 05-95% eluent B over 3.5 minutes

Flow: 1.5 ml/min

Column: Waters XTerra MS C₁₈ 5 μm 4.6×50 mm

Basic Analytical Conditions 2:

Eluent A. H₂O (10 mM NH₄HCO₃ buffer adjusted to pH=9.5 with NH₄OH)

Eluent B: CH₃CN

Gradient: 05-95% eluent B over 3.5 minutes

Flow: 0.8 ml/min

Column: Thermo Hypersil-Keystone BetaBasic-18 5 μm, 50×2.1 mm

Basic Analytical Conditions 3:

Eluent A: H₂O (10 mM NH₄HCO₃ buffer adjusted to pH=9.5 with NH₄OH)

Eluent B: CH₃CN

Gradient: 05-95% eluent B over 3.5 minutes

Flow: 0.8 ml/min

Column: Phenomenex Luna C18(2) 5 μm, 50×2.0 mm

Basic Analytical Conditions 4:

Eluent A. H₂O (10 mM NH₄HCO₃ buffer adjusted to pH=9.2 with NH₄OH)

Eluent B: CH₃CN

Gradient: 05-95% eluent B over 15 minutes

Flow: 0.8 ml/mm

Column: Phenomenex Luna C18(2) 5 μm, 150×2.0 mm

Polar Analytical Conditions:

Eluent A: H₂O (0.1% Formic Acid)

Eluent B: CH₃CN (0.1% Formic Acid)

Gradient: 00-50% eluent B over 3 minutes

Flow: 1.5 ml/min

Column: Phenomenex Synergi 4μ Hydro 80A, 50×4.6 mm

MS Conditions:

-   Capillary voltage: 3.5 kV or 3.6 kV-   Cone voltage: 30 V-   Source Temperature: 120° C.-   Scan Range: 165-700 amu-   Ionisation Mode: Electro Spray Negative, Positive or Positive &    Negative    FractionLynx System    System: Waters FractionLynx (dual analytical/prep)    HPLC Pump: Waters 2525    Injector-Autosampler: Waters 2767    Mass Spec Detector: Waters-Micromass ZQ    PDA Detector: Waters 2996 PDA    Acidic Analytical Conditions:    Eluent A. H₂O (0.1% Formic Acid)    Eluent B: CH₃CN (0.1% Formic Acid)    Gradient: 5-95% eluent B over 5 minutes    Flow: 2.0 ml/min    Column: Phenomenex Synergi 4μ Max-RP 80A, 50×4.6 mm    Polar Analytical Conditions:    Eluent A: H₂O (0.1% Formic Acid)    Eluent B: CH₃CN (0.1% Formic Acid)    Gradient: 00-50% eluent B over 5 minutes    Flow: 2.0 ml/min    Column: Phenomenex Synergi 4μ Max-RP 80A, 50×4.6 mm    MS Parameters for Acidic and Polar Analytical Conditions:    Capillary voltage: 3.5 kV    Cone voltage: 25 V    Source Temperature: 120° C.    Scan Range: 125-800 amu    Ionisation Mode: Electro Spray Positive or Electro Spray Positive &    Negative    Chiral Analytical Conditions:    Eluent: MeOH+0.1% NH₄/TFA    Flow: 1.2 ml/min    Total time: 16.00 min    Inj. Volume: 10 μL    Sample conc.: 2 mg/ml    Column: Astec, Chirobiotic V; 250×4.6 mm    Mass spectrometer was taken off-line.    Agilent System    HPLC System: Agilent 1100 series    Mass Spec Detector: Agilent LC/MSD VL    Multi Wavelength Detector: Agilent1100 series MWD    Software: HP Chemstation    Chiral Analytical Conditions:    Eluent: MeOH+0.2% NH₄/AcOH at room Temperature    Flow: 2.0 ml/min    Total time: 8.5 min    Inj. Volume: 20 uL    Sample Cone: 2 mg/ml    Column: Astec, Chirobiotic V; 250×4.6 mm    Chiral Preparative Conditions 1:    Eluent: MeOH+0.1% NH₄/TFA at room Temperature    Flow: 6.0 ml/min    Total time: 10 min    Inj. Volume: 100 uL    Sample Cone: 20 mg/ml    Column: Astec, Chirobiotic V; 250×10 mm    Chiral Preparative Conditions 2:    Eluent: MeOH+0.2% NH₄/AcOH at room Temperature    Flow: 20.0 ml/min    Total time: 19 min    Inj. Volume: 950 uL    Sample Cone: 25 mg/ml    Column: Astec, Chirobiotic V2; 250×21.2 mm    MS Conditions (Just Analytical Method):    Capillary voltage: 3000 V    Fragmentor: 150    Gain: 1.00    Drying gas: 12.0 L/min    Drying gas T: 350° C.    Nebulizer pressure: 35 (psig)    Scan Range: 125-800 amu    Ionisation Mode: Electro Spray Positive

In the examples below, the following key is used to identify the LCMSconditions used:

PS-A Platform System — acidic analytical conditions 1 PS-A2 PlatformSystem — acidic analytical conditions 2 PS-A3 Platform System — acidicanalytical conditions 3 PS-B Platform System — basic analyticalconditions 1 PS-B2 Platform System — basic analytical conditions 2 PS-B3Platform System — basic analytical conditions 3 PS-B4 Platform System —basic analytical conditions 4 PS-P Platform System — polar analyticalconditions FL-A FractionLynx System — acidic analytical conditions FL-PFractionLynx System — polar analytical conditions FL-C FractionLynxSystem — chiral analytical conditions AG-CA Agilent System — chiralanalytical conditions AG-CP1 Agilent System — chiral preparativeconditions 1 AG-CP2 Agilent System — chiral preparative conditions 2

Example 1 2-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

To a suspension of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride(134 mg, 0.5 mmol, 1.0 equiv.) (Array PPA-Q02-1) in toluene (0.8 ml) wasadded bis(tri-t-butylphosphine)palladium (0) (3 mg, 1 mol %) (Strem) andthe mixture was purged with nitrogen. A suspension of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (107 mg,0.55 mmol, 11 equiv.) (Aldrich 52,505-7) in ethanol (0.8 ml) was addedfollowed by potassium carbonate (415 mg, 3.0 mmol, 6 equiv.) in water(2.5 ml). The mixture was purged with nitrogen and sealed. The reactionmixture was heated in a CEM Explorer™ microwave to 135° C. for 15minutes using 50 watts power. The solvents were removed and the residuewas partitioned between ethyl acetate and 2N NaOH. The aqueous layer wasextracted with ethyl acetate and the combined organic layers were washedwith brine, dried (MgSO₄) and concentrated under reduced pressure. Thecrude reaction mixture was purified by column chromatography (SiO₂),eluting with a mixture of dichloromethane (90 ml):methanol (18ml):acetic acid (3 ml):H₂O (2 ml) to afford the title compound 14 mg(9%); LCMS (PS-A) R_(t) 1.79 min; m/z [M+H]⁺ 264.

Example 2 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile 2A.2-(3-Bromo-phenyl)-3-phenyl-propionitrile

A solution of 40% KOH (2.83 g in 5.0 ml of H₂O) in ethanol (13 ml) wasadded to a solution of benzaldehyde (2.85 ml, 28.05 mmol) and3-bromophenylacetonitrile (5 g, 25.50 mmol) in ethanol (9 ml). Thereaction mixture was then stirred at room temperature for 2 hours andthe precipitate was collected by suction filtration and washed with coldethanol (6.68 g, 92%). The crude product (3.45 g, 12.14 mmol) was thendissolved in ethanol (35 ml) and heated to 65° C. Sodium borohydride(459 mg, 12.14 mmol) was added in portions and the reaction mixture wasmaintained at this temperature for a further 2 hours. Upon cooling,water (10 ml) was added and the solvent was removed under reducedpressure. The residue was partitioned between water (100 ml) and ethylacetate (100 ml). The organic layer was separated, dried (MgSO₄),filtered and concentrated to afford the desired product (1.80 g, 52%),which was used without purification.

2B. 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile

2-(3-Bromo-phenyl)-3-phenyl-propionitrile was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. (LC/MS:(PS-A) R_(t) 2.98 [M+H]⁺ 274).

Example 32-[4-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine

Following the procedure of Example 1 but using3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(Boron Molecular D03-BM152) instead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave thetitle compound. (LC/MS: (PS-A) R_(t) 1.79 [M+H]⁺ 292.

Example 4 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

Following the procedure of Example 1 but using2,2-bis-(4-chloro-phenyl)-ethylamine in place of2-(4-chlorophenyl)-2-phenylethylamine hydrochloride* gave the titlecompound. (LC/MS: (PS-A) R_(t) 1.99 [M+H]⁺ 298). *This starting materialcan be made by the method described in J. Amer. Chem. Soc., 1983, 105,3183-3188.

Example 52-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine 5A.2-(3-Bromo-phenyl)-1-phenyl-ethylamine

Benzonitrile (500 mg, 4.849 mmol) was added dropwise to a solution of3-bromobenzylmagnesium bromide (0.275 M solution in diethyl ether, 21.1ml, 5.818 mmol) under an atmosphere of nitrogen at room temperature. Thereaction mixture was then heated to reflux for a period of 2 hours thenallowed to cool. Lithium aluminium hydride (1.0 M in THF, 4.85 ml, 4.849mmol) was then added cautiously and the reaction mixture was allowed toheat at reflux for a further 16 hours. Upon cooling, the reaction wasquenched by cautious and dropwise addition of water (5 ml) and thenpartitioned between water (20 ml) and ethyl acetate (100 ml). Theorganic layer was separated, dried (MgSO₄), filtered and concentrated.Purification by ion exchange chromatography afforded the desiredcompound (420 mg, 31%).

5B. 2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine

The product of 5B was reacted with3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.(LC/MS: (PS-B) R_(t) 2.54 [M+H]⁺ 292).

Example 6 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propylamine

To a solution of the product of Example 2 (70 mg, 0.256 mmol, 1.0 equiv)in ethanol (25 ml) was added concentrated ammonia (0.5 ml) and RaneyNickel (approximately 0.5 ml of the water suspension) and the reactionmixture was subjected to a hydrogen atmosphere for 17 hours. The mixturewas filtered through Celite® and the mother liquor was concentratedunder reduced pressure to give the title compound which was purified bypreparative liquid chromatography. (LC/MS: (PS-A) R_(t) 1.89 [M+H]⁺ 278.

Example 7 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine 7A.2-(4-Bromo-phenyl)-3-phenyl-propionitrile

Following the procedure described in Example 2A but substituting4-bromophenylacetonitrile for 3-bromophenylacetonitrile gave the titlecompound was obtained which was used in the next step without furtherpurification.

7B. 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propionitrile

By following the procedure described in Example 1 but substituting2-(4-Bromo-phenyl)-3-phenyl-propionitrile for2-(4-chlorophenyl)-2-phenylethylamine, the title compound was obtained.

7C. 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

The nitrile product of Example 7B was reduced using the conditionsdescribed m Example 6 to give the title compound. (LC/MS: (PS-B) R_(t)3.03 [M+H]⁺ 278.

Example 8{3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine8A. 3-(4-Bromo-phenyl)-2-cyano-acrylic acid ethyl ester

-   (J. Med. Chem, 1983, 26, 935-947)

4-Bromobenzaldehyde (3 g, 16.21 mmol) and ethyl cyanoacetate (1.9 ml,17.84 mmol) in toluene was added piperidine (27 μl) and the reactionmixture was refluxed for 1 hour with a Dean-Stark separator. The solventwas removed under reduced pressure, the residue triturated with warmethyl acetate, filtered to yield the desired product as a yellow solid(4.03 g, 89% yield). LC/MS: (PS-A2) R_(t) 3.44.

8B. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionic acid ethylester

A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (1.5g, 5.36 mmol) in dry toluene (12 ml) was added dropwise to4-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran, 6.96ml, 6.96 mmol) at 0° C. The reaction mixture was heated to 85° C. for 3hours, poured onto ice, acidified with 1N HCl and extracted with ethylacetate. The organic layer was separated, dried (MgSO₄), filtered andconcentrated, the crude product was purified over flash silicachromatography eluting with petroleum ether to ethyl acetate/petroleumether (5:95) to afford the desired product (1.91 g, 91% yield). LC/MS:(PS-A2) R_(t) 3.78 [M+H]⁻ 391.93.

8C. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid

A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionicacid ethyl ester (1.91, 4.87 mmol), acetic acid (10 ml), concentratedsulfuric acid (5 ml) and water (5 ml) were refluxed for 2 hours.Reaction mixture was poured into iced water and extracted with ethylacetate. The organic layer was separated, dried (MgSO₄), filtered andconcentrated, the crude product was purified over flash silicachromatography eluting with ethyl acetate/petroleum ether (1:1) toafford the desired product (0.82 g, 50% yield). LC/MS: (PS-A2) R_(t)3.39 [M+H]⁻ 338.86.

8D. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide

A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-prop ionic acid(0.25 g, 0.74 mmol) and 1-hydroxybenatriazole (0.12 g, 0.88 mmol) indichloromethane (3 ml) was stirred for 15 minutes before addition ofmethylamine (40% solution in water, 0.11 μl, 1.47 mmol) and1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.17 g, 0.88mmol). The reaction mixture was stirred for 16 hours, solvent removedunder reduced pressure and the residue partitioned between ethyl acetateand 1N HCl. The organic layer was separated, washed with saturatedsodium hydrogen carbonate, brine, dried (MgSO₄), filtered andconcentrated to yield the title compound which was used in the next stepwithout further purification. LC/MS: (PS-A2) R_(t) 3.20 [M+H]⁺ 353.95.

8E. [3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine

Under a nitrogen atmosphere, the crude3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide was cooledto 0° C., lithium aluminum hydride (0.075 g, 1.97 mmol) and diethylether (3 ml) were added. With cooling, aluminum chloride (0.23 g, 1.69mmol) was dissolved in diethyl ether (2 ml) and added. The reactionmixture was stirred for 16 hours, quenched with addition of water,basified (2N NaOH) and extracted with ethyl acetate. The organic layerwas separated, dried (MgSO₄), filtered and concentrated, the crudeproduct was purified over Phenomenex_Strata_SCX column chromatographyeluting with methanol followed by 2N ammonia in methanol to afford thedesired product (0.254 g, 62% yield for steps 1D and 1E combined).LC/MS: (PS-B3) R_(t) 3.20 [M+H]⁺ 339.85.

8F.{3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine was reactedwith 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-B3) R_(t) 2.63 [M+H]⁺ 326.00. ¹H NMR (Me-d₃-OD) δ 2.37-2.47(2H, m), 2.66 (3H, s), 2.91 (2H, t), 4.05 (1H, t), 7.25-7.34 (6H, m),7.54 (2H, d), 7.92 (2H, s), 8.51 (1H, br s—due to formic acid).

Example 9{3-(3,4-Difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine9A. 3-(4-Bromo-phenyl)-3-(3,4-difluoro-phenyl)-N-methyl-propionamide

By following the procedure described in Example 8A through to Example 8Cbut substituting 4-chlorophenylmagnesium bromide for3,4-difluorophenylmagnesium bromide, the title compound was obtained.LC/MS: (PS-A2) R_(t) 3.12 [M+H]⁺ 355.84.

9B.3-(3,4-Difluoro-phenyl)-N-methyl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide

3-(4-Bromo-phenyl)-3-(3,4-difluoro-phenyl)-N-methyl-propionamide wasreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-A2) R_(t) 2.55 [M+H]⁺ 341.93.

9C.{3-(3,4-Difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

Lithium aluminium hydride was added to a suspension of3-(3,4-Difluoro-phenyl)-N-methyl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamidein diethyl ether, followed by a solution of aluminium chloride indiethyl ether at 0° C., under a nitrogen atmosphere. Toluene was addedand the reaction mixture was heated at 70° C. for 18 hours. Upon coolingthe reaction was quenched with addition of water, basified (2N NaOH) andextracted with ethyl acetate. The organic layer was separated, dried(MgSO₄), filtered and concentrated to afford the desired compound.LC/MS: (PS-A2) R_(t) 2.15 [M+H]⁺ 328.06. ¹H NMR (Me-d₃-OD) δ 2.19-2.29(2H, m), 2.35 (3H, s), 2.51 (2H, t), 4.00 (1H, t), 7.06-7.24 (3H, m),7.27 (2H, d), 7.52 (2H, d), 7.92 (2H, s).

Example 10{3-(3-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 3-chlorophenylmagnesium bromide, thetitle compound was obtained. LC/MS: (PS-B3) R_(t) 2.67 [M+H]⁺ 326.00. ¹HNMR (Me-d₃-OD) δ 2.43-2.50 (2H, m), 2.68 (3H, s), 2.94 (2H, m), 4.13(1H, t), 7.24 (1H, m), 7.27-7.36 (3H, m), 7.41 (2H, d), 7.66 (2H, d),8.50 (2H, s).

Example 113-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide

By following the procedure described in Example 9A and 9B butsubstituting 3,4-difluorophenylmagnesium bromide for4-chlorophenylmagnesium bromide, the title compound was obtained. LC/MS:(PS-A2) R_(t) 2.54 [M+H]⁺ 326. ¹H NMR (Me-d₃-OD) δ 2.95 (2H, d), 4.53(1H, t), 7.27 (6H, m), 7.50 (2H, d), 7.91 (2H, s).

Example 123-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine 12A.3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionamide

A solution of 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid*(0.25 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.24 g, 1.47 mmol) indichloromethane was stirred for 45 minutes before the addition ofammonia (2M solution in methanol, 3.68 ml, 7.36 mmol). The reactionmixture was stirred for 2 hours, solvent removed under reduced pressureand residue was purified over flash silica chromatography eluting withethyl acetate/petroleum ether (1:4) to afford the title compound (0.091g, 36% yield). LC/MS: (PS-A2) R_(t) 3.08 [M+H]⁺ 339.93. *This startingmaterial can be made by the method described in Example 8A through to8C.

12B. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine

By following the procedure described in Example 8E but substituting3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionamide for3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide, the titlecompound was obtained. LC/MS: (PS-B2) R_(t) 3.88 [M+H]⁺ 359.87.

12C. 3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-B3) R_(t) 2.54 [M+H]⁺ 312.04. ¹H NMR (Me-d₃-OD) δ 2.39 (2H, m), 2.84(2H, t), 4.06 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.91 (2H, s).

Example 133-(3,4-Dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 12 but substituting4-chlorophenylmagnesium bromide for 3,4-dichlorophenylmagnesium bromide,the title compound was obtained. LC/MS: (PS-A2) R_(t) 2.17 [M+H]⁺345.95. ¹H NMR (Me-d₃-OD) δ 2.39 (2H, m), 2.84 (2H, t), 4.07 (1H, t),7.24-7.31 (4H, m), 7.45-7.49 (2H, m), 7.56 (2H, d), 7.93 (2H, s).

Example 14 4-(4-Chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine14A. 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine

A suspension of 4-(4-Bromo-phenyl)-piperidin-4-ol (4.02 g, 15.7 mmol) inchlorobenzene (30 ml) was added dropwise to a suspension of aluminiumchloride (7.32 g, 54.9 mmol) in chlorobenzene (10 ml) at 0° C. Thereaction mixture was stirred at 0° C. for 2 hours, quenched by additionof ice then methyl t-butyl ether added. After stirring for 1 hour theprecipitate was collected by filtration washed with water, methylt-butyl ether and water to afford the title compound (5.59 g, 92%yield). LC/MS: (PS-B3) R_(t) 3.57 [M+H]⁺ 350, 352.

14B. 4-(4-Chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-A3) R_(t) 7.22 [M+H]⁺ 338.08. ¹H NMR (Me-d₃-OD) δ 2.64-2.74 (4H, m),3.22-3.25 (4H, m), 7.33-7.45 (6H, m), 7.65 (2H, d), 8.37 (2H, s).

Example 154-(4-Methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 14 but substitutingchlorobenzene for anisole, the title compound was obtained. LC/MS:(PS-B3) R_(t) 2.42 [M+H]⁺ 334.00. ¹H NMR (Me-d₃-OD) δ 2.69 (4H, m), 3.23(4H, m), 3.76 (3H, s), 6.90 (2H, d), 7.28 (2H, d), 7.40 (2H, d), 7.65(2H, d), 8.53 (2H, s).

Example 164-(4-Chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine16A. 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidethyl ester

To a stirring suspension of4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine* (0.28 g, 0.80 mmol)in dichloromethane (10 ml), were added triethylamine (0.45 ml, 3.2 mmol)and ethyl chloroformate (0.085 ml, 0.88 mmol). The reaction mixture wasstirred for 3 hours, diluted with ethyl acetate and washed with 1N HCl,saturated sodium hydrogen carbonate and brine. The organic layer wasseparated, dried (MgSO₄), filtered and concentrated to afford the titlecompound (0.29 g, 94% yield). LCMS: (PS-A2), R_(t) 4.02 [M+H]⁺ 422, 424.*This starting material can be made by the method described in Example14A

16B. 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine

Under a nitrogen atmosphere4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidethyl ester (0.28 g, 0.66 mmol) and lithium aluminum hydride (0.051 g)were suspended in tetrahydrofuran (5 ml) and stirred for 2 hours. Thereaction mixture was quenched with addition of water, solvent removedunder reduced pressure, the residue was partitioned between ethylacetate and 2N NaOH. The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated to afford the desired product (0.241g, 99% yield). LC/MS: (PS-B3) R_(t) 3.78 [M+H]⁺ 363.95, 365.73.

16C.4-(4-Chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine was reactedwith 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-B3) R_(t) 2.90 [M+H]⁺ 352. ¹H NMR (Me-d₃-OD) δ 2.41-2.53 (2H,m), 2.82 (3H, d), 2.97-3.12 (4H, m), 3.56-3.59 (2H, m), 7.28 (2H, s),7.34 (1H, m), 7.42 (1H, d), 7.49 (1H, d), 7.54 (1H, d), 7.61 (1H, d),7.75 (1H, d), 8.52 (2H, d).

Example 17 4-Phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for4-(4-Chloro-phenyl)-4-phenyl-piperidine, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 1.88 [M+H]⁺ 304. ¹H NMR (Me-d₃-OD) δ2.65-2.71 (4H, m), 3.21 (4H, t), 7.18-7.22 (1H, m), 7.32-7.38 (6H, m),7.55 (2H, d), 7.93 (2H, s).

Example 184-[4-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-4-phenyl-piperidine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4-chloro-phenyl)-4-phenyl-piperidine and3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole,the title compound was obtained. LC/MS: (PS-A2) R_(t) 2.95 [M+H]⁺ 315.¹H NMR (Me-d₃-OD) δ 2.22 (6H, s), 2.66-2.76 (4H, m), 3.16-3.28 (4H, m),7.19-7.44 (9H, m).

Example 19

Dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for brompheniraminemaleate, the title compound was obtained. LC/MS: (PS-B2) R_(t) 2.29[M+H]⁺ 307. ¹H NMR (Me-d₃-OD) δ 2.44-2.54 (1H, m), 2.59-2.70 (1H, m),2.77 (6H, s), 2.93-3.01 (2H, m), 4.20 (1H, t), 7.25-7.28 (1H, m),7.32-7.36 (3H, m), 7.54 (2H, d), 7.75 (1H, dt), 7.94 (2H, br s).

Example 20{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine20A. 2,2-Bis-(4-chloro-phenyl)-N,N-dimethyl-acetamide

Bis-(4-chloro-phenyl)-acetic acid was reacted with dimethylaminefollowing the procedure set out in Example 8D to give the titlecompound. LC/MS: (PS-A2) R_(t) 3.40 [M+H]⁺ 309.95.

20B. [2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-amine

By following the procedure described in Example 8E but substituting3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide for2,2-Bis-(4-chloro-phenyl)-N,N-dimethyl-acetamide, the title compound wasobtained. LC/MS: (PS-B2) R_(t) 3.75 [M+H]⁺ 295.99.

20C.{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine

[2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-amine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-B2) R_(t) 3.07 [M+H]⁺ 325.99. ¹H NMR (Me-d₃-OD) δ 2.5 (6H, s), 2.98(2H, dd), 4.34 (1H, t), 7.31-7.36 (6H, m), 7.50 (2H, d), 7.92 (2H, s).

Example 21{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 20 but substitutingdimethylamine for methylamine, the title compound was obtained. LC/MS:(PS-B2) R_(t) 2.83 [M+H]⁺ 312.07. ¹H NMR (Me-d₃-OD) δ 2.42 (3H, s),3.20-3.23 (2H, dd), 4.18 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.92(2H, br s).

Example 22{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(R)

Prepared using the same procedure as Example 21 but enantiomersseparated by chiral preparative HPLC using method AG-CP2. LCMS: (AG-CA)R_(t) 5.58 min, 97.4% ee. ¹H NMR (Me-d₃-OD) δ 2.75 (3H, s), 3.78 (2H,d), 4.43 (1H, t), 7.39 (4H, s), 7.44 (2H, d), 7.69 (2H, d), 8.43 (2H,s).

Example 23{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(S)

Prepared using the same procedure as Example 21 but enantiomersseparated by chiral preparative HPLC using method AG-CP2. LCMS: (AG-CA)R_(t) 4.51 min, 98.0% ee. ¹H NMR (Me-d₃-OD) δ 2.75 (3H, s), 3.79 (2H,d), 4.51 (1H, t), 7.37-7.43 (4H, m), 7.49 (2H, d), 7.73 (2H, d), 8.66(2H, s).

Example 244-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-morpholine

By following the procedure described in Example 20 but substitutingdimethylamine for morpholine, the title compound was obtained. LC/MS:(PS-B3) R_(t) 3.07 [M+H]⁺ 368.05. ¹H NMR (Me-d₃-OD) δ 2.50 (4H, m), 2.97(2H, m), 3.60 (4H, t), 4.26 (1H, t), 7.27 (6H, m). 7.49 (2H, d), 7.89(2H, s).

Example 254-{4-[1-(4-Chloro-phenyl)-2-pyrrolidin-1-yl-ethyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 20 but substitutingdimethylamine for pyrrolidine, the title compound was obtained. LC/MS:(PS-A2) R_(t) 2.06 [M+H]⁺ 354.01. ¹H NMR (Me-d₃-OD) δ 1.85 (4H, m), 2.87(4H, m), 3.47 (2H, d), 4.31 (1H, t), 7.30-7.37 (6H, m), 7.54 (2H, d),7.92 (2H, s).

Example 26{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-amine

By following the procedure described in Example 20 but substitutingdimethylamine for isopropylamine, the title compound was obtained.LC/MS: (PS-A2) R_(t) 2.10 [M+H]⁺ 340. ¹H NMR (Me-d₃-OD) δ 1.31 (6H, d),3.38-3.45 (1H, m), 3.65-3.74 (2H, m), 4.39 (1H, br t), 7.37 (6H, m),7.59 (2H, d), 7.94 (2H, s).

Example 27Dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

By following the procedure described in Example 20, the title compoundwas obtained. LC/MS: (PS-B2) R_(t) 2.82 [M+H]⁺ 292.11. ¹H NMR (Me-d₃-OD)δ 2.25 (6H, s), 2.95-3.04 (2H, m), 4.20 (1H, t), 7.16 (1H, t), 7.26-7.33(6H, m), 7.49 (2H, d), 7.89 (2H, s).

Example 28 {2,2-Bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine

By following the procedure described in Example 20, the title compoundwas obtained. LC/MS: (PS-B2) R_(t) 2.45 [M+H]⁺ 358.11. ¹H NMR (Me-d₃-OD)δ 2.69 (6H, s), 3.59 (2H, d), 4.43 (1H, t), 7.39 (4H, d), 7.57 (4H, d),7.93 (4H, s).

Example 29 5 {2,2-Bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 21, the title compoundwas obtained. LC/MS: (PS-B2) R_(t) 2.18 [M+H]⁺ 344.11. ¹H NMR (Me-d₃-OD)δ 2.65 (3H, s), 3.60 (2H, d), 4.34 (1H, t), 7.36 (4H, d), 7.59 (4H, d),7.94 (4H, s).

Example 30 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine(R)

Prepared using the same procedure as Example 4 but enantiomers separatedby chiral preparative HPLC using method AG-CP1. LCMS: (FL-C) R_(t) 10.97min, 95.7% ee. ¹H NMR (Me-d₃-OD) δ 3.65 (2H, m), 4.30 (1H, t), 7.35-7.40(6H, m), 7.64 (2H, d), 8.16 (2H, s).

Example 31 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine(S)

Prepared using the same procedure as Example 4 but enantiomers separatedby chiral preparative HPLC using method AG-CP1. LCMS: (FL-C) R_(t) 9.63min, 100% ee. ¹H NMR (Me-d₃-OD) δ 3.66 (2H, m), 4.30 (1H, t), 7.35-7.40(6H, m), 7.64 (2H, d), 8.15 (2H, s).

Example 32 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide

By following the procedure described in Example 12A followed by 12C butsubstituting 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid forBis-(4-chloro-phenyl)-acetic acid, the title compound was obtained.LC/MS: (PS-A2) R_(t) 2.53 [M+H]⁺ 312. ¹H NMR (Me-d₃-OD) δ 4.99 (1H, s),7.30-7.33 (6H, m), 7.55 (2H, d), 7.86-8.02 (2H, br s).

Example 331-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperazine37A. Bis-(4-chloro-phenyl)-acetaldehyde

Dess-Martin periodinane (3.17 g, 7.49 mmol) was added to a solution of2,2-Bis-(4-chloro-phenyl)-ethanol in dichloromethane (40 ml). Thereaction mixture was stirred at room temperature for 17 hours undernitrogen, 2N NaOH added (15 ml) and the organic layer was separated,dried (MgSO4), filtered and concentrated to afford the title compoundswhich was used in the next step without further purification. LC/MS:(PS-B3) R_(t) 3.62 [M+H]⁺ 262.91.

33B. 4-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester

To a solution of bis-(4-chloro-phenyl)-acetaldehyde (3.74 mmol) inmethanol under a nitrogen atmosphere, N-BOC-piperazine (1.05 g, 5.61mmol) was added ???, the reaction mixture was stirred for 1 hour beforeaddition of sodium cyanoborohydride (0.28 g, 4.49 mmol). The reactionmixture was stirred for 18 hours, water added (3 ml) and the solventremoved under reduced pressure. The residue was partitioned betweendichloromethane and water, the organic layer was separated, dried(MgSO4), filtered and concentrated. Purified over flash silicachromatography eluting with ethyl acetate/petroleum ether (3:7) to yieldthe title compound (0.18 g, 11% yield for steps 30A and 30B combined).LC/MS: (PS-A2) R_(t) 2.66 [M−BOC+H]⁺ 335.02.

33C. 1-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine

4-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester was treated with HCl in ethyl acetate (saturated, 5 ml)for 1 hour, solvent removed under reduced pressure to afford the titlecompound as the HCl salt

33D.1-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperazine

1-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-B3) R_(t) 2.63 [M+H]⁺ 326.00. ¹H NMR (Me-d₃-OD) δ 3.55-3.68 (8H, m),3.74 (1H, t), 4.10-4.17 (2H, m), 7.39 (2H, d), 7.48 (2H, d), 7.54 (2H,d), 7.70 (2H, d), 8.57 (2H, br s).

Example 341-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperidine

By following the procedure described in Example 33A, 33B and 33D butsubstituting piperidine for N-BOC-piperazine, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 2.21 [M+H]⁺ 366.09. ¹H NMR (Me-d₃-OD) δ1.44 (2H, m), 1.53 (4H, m), 2.39-2.57 (4H, m), 2.94-3.09 (2H, m), 4.26(1H, t), 7.22-7.35 (6H, m), 7.50 (2H, d), 7.91 (2H, s).

Example 354-{4-[2-Azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole35A. 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

2,2-Bis-(4-chloro-phenyl)-ethanol was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-A2) R_(t) 2.72 [M+H]⁺ 299.00.

35B. (4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde

By following the procedure described in Example 33A but substituting2,2-Bis-(4-chloro-phenyl)-ethanol for2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol, the titlecompound was obtained. LC/MS: (PS-B3) R_(t) 2.97 [M+H]⁻ 294.98.

35C.4-{4-[2-Azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 33B but replacingbis-(4-chloro-phenyl)-acetaldehyde and N-BOC-piperazine with(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde andazetidine, the title compound was obtained. LC/MS: (PS-B3) R_(t) 2.99[M+H]⁺ 338.09. ¹H NMR (Me-d₃-OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m),3.71-3.77 (1H, m), 4.01 (2H, m), 4.14 (2H, m), 4.40 (1H, t), 7.40 (4H,br s), 7.49 (2H, d), 7.73 (2H, d), 8.69 (2H, br s).

Example 36 1-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

By following the procedure described in Example 5 but replacing3-bromobenzylmagnesium bromide and3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolewith 4-bromobenzylmagnesium bromide and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the titlecompound was obtained. LC/MS: (PS-B2) R_(t) 2.44 [M+H]⁺ 264.04. ¹H NMR(Me-d₃-OD) δ 2.99 (2H, d), 4.13 (1H, t), 7.10 (2H, d), 7.20-7.38 (5H,m), 7.45 (2H, d), 7.91 (2H, s).

Example 37[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-acetonitrile37A.4-Bromo-5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazole

To a solution of 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole (1.4 g,6.2 mmol, 1.0 equiv) in chloroform (31 ml) was added p-toluene sulphonicacid monohydrate (118 mg, 0.62 mmol, 0.1 equiv). The solution was cooledto 0° C. and 3,4-dihydro-2H-pyran (0.85 ml, 9.3 mmol, 1.5 equiv) wasadded drop-wise over 5 minutes. The mixture was allowed to warm to roomtemperature for 1 hour and the solvents were removed under reducedpressure. The crude mixture was purified by column chromatography(SiO₂), eluting with 0→25% EtOAc-petrol over a linear gradient to affordthe title compound 1.4 g (59%), LCMS (PS-A) R_(t) 3.72 min [M+H]⁺ 314.

37B.{4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-phenyl}-acetonitrile

The product of Example 37A,4-bromo-5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazole,was reacted with 4-(cyanomethylphenyl)boronic acid (Combi-Blocks, SanDiego, USA Cat. No. 2444-001) under the conditions described in Example1, to give the title compound.

37C.[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-acetonitrile

To{4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-phenyl}-acetonitrile(Example 8B) (35 mg, 0.1 mmol, 1.0 equiv) in ethyl acetate (1 ml) wasadded HCl in ethyl acetate (1 ml) and the mixture was stirred for 1hour. The solvents were removed under reduced pressure and the titlecompound was purified by column chromatography (SiO₂) eluting with alinear gradient (0-30% ethyl acetate-petrol) 16 mg (60%); LCMS (PS-A)R_(t) 2.85 min [M+H]⁺ 266.

37D. Preparation of Compounds of the Formula (I) from[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-acetonitrile

(i) The product of Example 37B can be reacted with benzaldehyde underthe conditions described in Example 2 to give2-[4-(5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrilewhich can be deprotected by removal of the 1-tetrahydropyranyl groupunder the conditions set out in Example 37C to give2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrile.

2-[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrileor its 1-tetrahydropyranyl derivative can be reduced according to themethod of Example 6 (and thereafter where necessary deprotectedaccording to the method of Example 41C) to give2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propylamine.

The product of Example 37B can also be reacted with benzyl magnesiumbromide or phenyl magnesium bromide under the Grignard reactionconditions described in Example 5 to give (following deprotection by themethod of Example 37C)1-benzyl-2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-ethylamineand2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylaminerespectively.

Example 38 Construction of Pyrazole Ring System 38A. Synthesis of4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole

To 4-bromophenylacetone (5.0 g, 23.5 mmol, 1.0 equiv) (Acros Organics34216) was added N,N-dimethylformamide dimethyl acetal (11.3 ml, 84.6mmol, 3.6 equiv) and the mixture was heated to 90° C. for 6 hours. Thesolvents were removed and the resulting gum was dissolved in ethanol(235 ml) with additional heating. Hydrazine hydrate (1.37 ml, 28.2 mmol,1.2 equiv) was added and the mixture was heated to reflux for 15 hours.The solvents were removed under reduced pressure and the solid wastriturated with dichloromethane to afford the title compound, 2.24 g(40%); LCMS (PS-A) R_(t) 2.87 min [M+H]⁺ 238. Further material could beisolated from the mother liquor.

38B. Conversion of 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole to compoundsof the Formula (I)

(i) 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole can be protected at the1-position of the pyrazole ring by formation of the tetrahydropyranyl(THP) derivative by following the procedure set out in Example 38A. AGrignard reagent can then be prepared from the bromo-phenyl moiety bytreating the protected derivative with magnesium in an ether solvent instandard fashion (see J. March, Advanced Organic Chemistry, 4^(th)Edition, 1992, John Wiley, New York, pages 622-625). The Grignardreagent can be reacted with nitrostyrene (the nitrostyrene having beenprepared by a standard method such as the method described in OrganicSyntheses, Collective Volume 1, page 413) and the resulting nitroethylcompound reduced to give2-{4-[3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-phenyl}-2-phenyl-ethylamine.Removal of the tetrahydropyranyl group using the method of Example 8Cgives 2-{4-[3-methyl-1H-pyrazol-4-yl]-phenyl}-2-phenyl-ethylamine.(ii) The bromo-compound of Example 38A can be converted into compoundsof the formula (I) in which the group A contains a nitrogen atom whichis attached to the group E. The introduction of a nitrogen containingentity can be accomplished by reaction of the compound of Example 38Awith [3-(4-chloro-phenylamino)-propyl]-methyl-carbamic acid tert-butylester under palladium catalysed amination conditions of the typedescribed in Organic Letters, 2002, vol. 4, No. 17, pp 2885-2888,followed by removal of the t-butyloxycarbonyl protecting group bystandard methods.

Example 39 [3-(1H-Pyrazol-4-yl)-phenyl]-acetonitrile

By following the procedure set out in Example 1 but using3-bromophenylacetonitrile instead of2-(4-chlorophenyl)-2-phenylethylamine, the title compound was obtained.LCMS (PS-A) 2.35 min [M+H]⁺ 184.

3-(1H-Pyrazol-4-yl)-phenyl]-acetonitrile can be used as an intermediatein the preparation of compounds of the formula (I), for example by meansof an aldehyde condensation reaction as described in Example 2 or aGrignard reaction as described in Example 5.

Example 402-(4-Chloro-phenyl)-N-methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide

By following the procedure described in Example 12A followed by 12C butsubstituting 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid forBis-(4-chloro-phenyl)-acetic acid and ammonia for methyl amine, thetitle compound was obtained. LC/MS (PS-A2): R_(t)2.64 [M+H]⁺ 326. ¹H NMR(Me-d₃-OD) δ 2.79 (3H, s), 4.94, (1H, br s), 7.26-7.35 (6H, m),7.55-7.57 (2H, m), 7.96 (2H, br s)

Example 41 N-Methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide

By following the procedure described in Example 40, the title compoundwas obtained. LC/MS (PS-A2): R_(t)2.19 [M+H]⁺ 358. ¹H NMR (Me-d₃-OD) δ2.80 (3H, s), 4.95, (1H, br s), 7.32 (4H, d), 7.56 (4H, d), 7.98 (4H, brs)

Example 42{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine42A. 1-(4-Bromo-phenyl)-2-methylamino-ethanol

A solution of 2-(4-bromophenyl)-oxirane (0.5 g, 2.51 mmol) inmethylamine (6.6 ml, 33% by volume in ethanol, 25.12 mmol) was stirredat room temperature under an atmosphere of nitrogen. After 18 hours thesolvent was removed in vacuo and the residue was purified over flashsilica eluting with dichloromethane: methanol:acetic acid:water(120:15:3:2) to afford the desired compound as the acetic acid salt.Further purification over a Phenomenex_Strata_SCX column eluting withmethanol followed by 2N ammonia in methanol gave the desired product.LC/MS: (PS-B3) R_(t) 2.52 [M+H]⁺ 230.

42B. [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine

Aluminium chloride (278 mg, 2.087 mmol) was added portionwise to astirred solution of 1-(4-Bromo-phenyl)-2-methylamino-ethanol (160 mg,0.696 mmol) in chlorobenzene (3 ml) and the reaction mixture stirred atroom temperature for 17 hours. Water (2 ml) was added dropwise and thereaction mixture was then partitioned between dichloromethane (100 ml)and saturated NaHCO₃ (30 ml). The organic layer was dried (MgSO₄),filtered and concentrated under reduced pressure. The crude product wasthen purified by Phenomenex_Strata_SCX column chromatography elutingwith methanol followed by 2N ammonia in methanol to afford the desiredproduct. LC/MS: (PS-B3) R_(t) 3.58 [M+H]⁺ 324.

42C.{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

A solution of[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine (6.1 g,13.716 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.3 g,27.431 mmol) and K₃PO₄ (10.19 g, 48.00 mmol) in ethanol (7.5 ml),methanol (11.5 ml), toluene (7.5 ml) and water (11.5 ml) was purged withnitrogen for 2 minutes. Bis(tri-t-butylphosphine)palladium (0) (175 mg,2.5 mol %) was then added and the reaction mixture purged with nitrogenfor a further 2 minutes. The mixture was then heated to 80° C., undernitrogen for a period of 17 hours. The solvents were removed and theresidue was partitioned between ethyl acetate and 2N NaOH. The aqueouslayer was extracted with ethyl acetate and the combined organic layerswere washed with brine, dried (MgSO₄) and concentrated under reducedpressure. The crude reaction mixture was purified by columnchromatography (SiO₂), eluting with dichloromethane:methanol:aceticacid:water (90:18:3:2) to afford the title compound (3.6 g); LCMS(PS-A2) R_(t) 2.08 min [M+H]⁺ 312.

Example 43{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-ethyl-amine

By following the procedures described in Examples 42A through to 42C butsubstituting methylamine for ethylamine, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 2.11 [M+H]⁺ 326. ¹H NMR (Me-d₃-OD) δ 1.15(3H, t), 2.83 (2H, q), 3.35-3.43 (2H, m), 4.25 (1H, t), 7.30-7.48 (6H,m), 7.57 (2H, d), 7.95 (2H, s).

Example 444-{4-[1-(4-Chloro-phenyl)-2-imidazol-1-yl-ethyl]-phenyl}-1H-pyrazole

By following the procedures described in Examples 42A through to 42C butsubstituting methylamine for imidazole, the title compound was obtained.LC/MS-(PS-B3) R_(t) 2.73 [M+H]⁺ 349. ¹H NMR (d₆-DMSO) δ 4.60 (1H, t),4.95 (2H, d), 7.32 (2H, d), 7.42 (4H, s), 7.53-7.60 (3H, m), 7.70 (1H,s), 8.05 (2H, s), 9.0 (1H, s).

Example 45Methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine45A. [2-(4-Bromo-phenyl)-2-(4-phenoxy-phenyl)-ethyl]-methyl-amine

By following the procedure described in Example 42B but substitutingchlorobenzene for diphenyl ether and employing nitrobenzene as solvent,the title compound was obtained. LC/MS: (PS-A2) R_(t) 2.54 [M+H]⁺ 382.

45BMethyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

By following the procedure described in Example 42C but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for[2-(4-Bromo-phenyl)-2-(4-phenoxy-phenyl)-ethyl]-methyl-amine, the titlecompound was obtained. LC/MS: (PS-B3) R_(t) 3.04 [M+H]⁺ 370. ¹H NMR(Me-d₃-OD) δ 2.75 (3H, s), 3.75 (2H, d), 4.38 (1H, t), 6.98 (4H, dd),7.12 (1H, t), 7.33-7.40 (6H, m), 7.61 (2H, d), 7.95 (2H, s).

Example 46{2-(4-Methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine46A. [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine

By following the procedure described in Example 42B but substitutingchlorobenzene for anisole, the title compound was obtained as a mixtureof regioisomers (ca 4:1) with the corresponding ortho-methoxy analogue.LC/MS: (PS-B3) R_(t) 3.24 [M+H]⁺ 320.

46B. [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine

BOC₂O (941 mg, 4.309 mmol) was added to a solution of[2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine (and itsregioisomer) (1.38 g, 4.309 mmol) in dichloromethane (10 ml). Afterstirring at room temperature for 16 hours the solvent was removed underreduced pressure and the crude product was purified by flashchromatography eluting with ethyl acetate/petroleum ether (1:9) to yieldthe intermediate BOC protected compound as the desired single isomer(540 mg). The product was then stirred in a saturated solution of HCl indiethyl ether (30 ml) for 3 days. Removal of the solvent under reducedpressure afforded the title compound as the HCl salt. LC/MS: (PS-B3)R_(t) 3.21 [M+H]⁺ 320.

46C.{2-(4-Methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in example 42C but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for[2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine, the titlecompound was obtained. LC/MS: (PS-B3) R_(t) 2.52 [M+H]⁺ 308. ¹H NMR(Me-d₃-OD) δ 2.75 (3H, s), 3.75 (2H, dd), 3.80 (3H, s), 4.38 (1H, t),6.95 (2H, d), 7.32 (2H, d), 7.45 (2H, d), 7.70 (2H, d), 8.52 (2H, s).

Example 47Methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine47A. 4-[1-(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol

Boron tribromide (7.8 ml, 1.0M in dichloromethane) was added slowly to asolution of [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine(500 mg, 1.56 mmol) in dichloromethane (8 ml) at 0° C., under anatmosphere of nitrogen. The reaction mixture was allowed to warm to roomtemperature and then stirred for a further hour. The mixture was pouredon to ice and then diluted with dichloromethane and saturated NaHCO₃solution. The organic layer was dried (MgSO₄), filtered and concentratedto afford the desired product. LC/MS: (PS-B3) R_(t) 2.76 [M+H]⁺ 306.

47B. [2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamicacid tert-butyl ester

BOC₂O (269 mg, 1.23 mmol) was added to a solution of4-[1-(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol (360 mg, 1.18 mmol) indichloromethane (20 ml). After stirring at room temperature for 16 hoursthe solvent was removed under reduced pressure and the crude product waspurified by column chromatography (SiO₂), eluting with ethylacetate/petroleum ether (1:4) to yield the title compound. LC/MS: (FL-A)R_(t) 3.85 [M+H]⁺ 406.

47C{2-(4-Bromo-phenyl)-2-[4-(pyrazin-2-yloxy)-phenyl]-ethyl}-methyl-amine

A solution of[2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acidtert-butyl ester (125 mg, 0.31 mmol), 2-chloropyrazine (35.2 mg, 0.31mmol) and K₂CO₃ (213 mg, 1.54 mmol) in dimethylformamide (8 ml) washeated to 100° C. for 17 hours. Upon cooling, the solvent was removedunder reduced pressure and the residue was partitioned between ethylacetate and saturated NaHCO₃ solution. The organic layer was dried(MgSO₄), filtered and concentrated. The crude product was then treatedwith saturated HCl in diethyl ether (15 ml) and stirred at roomtemperature for 72 hours. The solvent was then removed under reducedpressure and the crude product was purified by Phenomenex_Strata_SCXcolumn chromatography eluting with methanol followed by 2N ammonia inmethanol to afford the desired product (82 mg). LC/MS: (PS-B3) R_(t)3.17 [M+H]⁺ 384.

47DMethyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

By following the procedure described in Example 42C, but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for{2-(4-Bromo-phenyl)-2-[4-(pyrazin-2-yloxy)-phenyl]-ethyl}-methyl-amine,the title compound was obtained. LC/MS: (PS-B3) R_(t) 2.48 [M+H]⁺ 372.¹H NMR (Me-d₃-OD) δ 2.80 (3H, s), 3.75-3.90 (2H, m), 4.50 (1H, t), 7.23(2H, d), 7.50 (4H, t), 7.75 (2H, d), 8.12 (1H, d), 8.33 (1H, d), 8.42(2H, s), 8.48 (1H, s).

Example 48 Methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine48A. [2-(4-Bromo-phenyl)-2-hydroxy-ethyl]-methyl-carbamic acidtert-butyl ester

BOC₂O (1.90 g, 8.69 mmol) was added to a solution of1-(4-Bromo-phenyl)-2-methylamino-ethanol (2.00 g, 8.69 mmol) indichloromethane (20 ml). After stirring at room temperature for 16 hoursthe solvent was removed under reduced pressure and the crude product waspurified by column chromatography (SiO₂), eluting with ethylacetate/petroleum ether (1:4) to yield the desired product (2.1 g).LC/MS: (PS-B3) R_(t) 3.16 [M+H]⁺ 330.

48B [2-(4-Bromo-phenyl)-2-phenoxy-ethyl]-methyl-amine

Diethyl azodicarboxylate (358 μl, 2.27 mmol) was added dropwise to asolution of [2-(4-Bromo-phenyl)-2-hydroxy-ethyl]-methyl-carbamic acidtert-butyl ester (500 mg, 1.51 mmol), triphenylphosphine (596 mg, 2.27mmol) and phenol (285 mg, 3.03 mmol) in tetrahydrofuran (10 ml) and thereaction mixture stirred at room temperature, under an atmosphere ofnitrogen, for 17 hours. The solvent was then removed under reducedpressure and the residue was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was dried (MgSO₄), filteredand concentrated. The crude product was then purified by columnchromatography (SiO₂), eluting with ethyl acetate/petroleum ether (1:9)to yield the intermediate BOC protected compound, which was then stirredin a saturated solution of HCl in diethyl ether (20 ml) for 24 hours.Removal of the solvent under reduced pressure afforded the titlecompound as the HCl salt. Further purification by Phenomenex_Strata_SCXcolumn chromatography, eluting with methanol followed by 2N ammonia inmethanol, afforded the desired product as the free base (94 mg). LC/MS:(PS-B3) R_(t) 4.04 [M+H]⁺ 406.

48C Methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

By following the procedure described in Example 42C, but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for[2-(4-Bromo-phenyl)-2-phenoxy-ethyl]-methyl-amine, the title compoundwas obtained. LC/MS: (PS-B3) R_(t) 2.73 [M−PhO+H]⁺ 200. ¹H NMR(Me-d₃-OD) δ 2.50 (3H, s), 2.90 (1H, dd), 3.15 (1H, dd), 5.40 (1H, dd),6.85 (1H, t), 6.90 (2H, d), 7.18 (2H, t), 7.40 (2H, d), 7.55 (2H, d),7.93 (2H, s).

Example 492-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine49A. (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol

4-Chlorophenylmagnesium bromide (12.97 ml, 1M solution in diethyl ether)was added slowly to a solution of 4-bromobenzaldehyde (2.0 g, 10.81mmol) in tetrahydrofuran (25 ml) at 0° C., under an atmosphere ofnitrogen. The reaction mixture was allowed to warm to room temperatureand was stirred for 17 hours. Water (3 ml) was then added and thesolvent was removed under reduced pressure. The residue was thenpartitioned between ethyl acetate and 1N HCl solution. The organic layerwas washed with brine, dried (MgSO₄), filtered and concentrated. Thecrude product was then purified by column chromatography (SiO₂), elutingwith ethyl acetate/petroleum ether (1:9), to yield the title compound(2.30 g). LC/MS: (PS-B3) R_(t) 3.49 [M−H]⁺ 297.

49B.2-{2-[(4-Bromo-phenyl)-(4-chloro-phenyl)-methoxy]-ethyl}-isoindole-1,3-dione

A mixture of (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol (2.3 g, 7.73mmol), N-(2-hydroxyethyl)phthalimide (1.4 g, 7.36 mmol) andpara-toluenesulphonic acid monohydrate (560 mg, 2.94 mmol) in toluene(50 ml) was heated to reflux under Dean-Stark conditions for 17 hours.Upon cooling, the solvent was removed and the residue was partitionedbetween ethyl acetate and water. The organic layer was then dried(MgSO₄), filtered and concentrated. The crude product was purified bycolumn chromatography (SiO₂), eluting with ethyl acetate/petroleum ether(1:4), to yield the title compound (1.95 g). LC/MS. (PS-B3) R_(t) 4.07no observable mass ion.

49C.N-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-phthalamicacid

By following the procedure described in Example 42C, but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for2-{2-[(4-Bromo-phenyl)-(4-chloro-phenyl)-methoxy]-ethyl}-isoindole-1,3-dione,the title compound was obtained. LC/MS: (FS-A) R_(t) 2.85 [M−H]⁺ 474.

49D.2-(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxyl-ethylamine

Hydrazine monohydrate (159 μl, 3.28 mmol) was added to a solution ofN-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-phthalamicacid (260 mg, 0.55 mmol) in methanol (6 ml) and the reaction mixturestirred at 80° C. for 16 hours. Upon cooling, the solvent was removedunder reduced pressure and the crude product was purified by columnchromatography (SiO₂), eluting with dichloromethane: methanol: aceticacid: water (90:18:3:2). Further purification by Phenomenex_Strata_SCXcolumn chromatography, eluting with methanol followed by 2N ammonia inmethanol, afforded the desired product as the free base (120 mg). LC/MS:(FL-A) R_(t) 2.07 [M−NH₂CH₂CH₂+H]⁺ 267. ¹H NMR (Me-d₃-OD) δ 2.85 (2H,t), 3.55 (2H, t), 5.45 (1H, s), 7.35-7.40 (6H, m), 7.58 (2H, d), 7.95(2H, s).

Example 504-{4-[1-(4-Chloro-phenyl)-3-pyrrolidin-1-yl-propyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 8 but substitutingmethylamine for pyrrolidine, the title compound was obtained. LC/MS:(PS-A2) R_(t) 2.25 [M+H]⁺ 366. ¹H NMR (Me-d₃-OD) δ 1.83-1.95 (2H, m),1.95-2.09 (2H, m), 2.4-2.5 (2H, m), 2.88-2.97 (2H, m), 3.02 (2H, dd),3.52-3.61 (2H, m), 4.02 (1H, t), 7.25 (4H, q), 7.32 (2H, d), 7.55 (2H,d), 8.41 (2H, s).

Example 514-{4-[3-Azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 8 but substitutingmethylamine for pyrrolidine, the title compound was obtained. LC/MS:(PS-A2) R_(t) 2.18 [M+H]⁺ 352. ¹H NMR (Me-d₃-OD) δ 2.12-2.25 (2H, m),3.00 (2H, t), 3.85-3.98 (5H, m), 4.05-4.17 (2H, m), 7.18 (21H, d), 7.19(4H, s), 7.45 (2H, d), 7.83 (2H, s).

Example 52Methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-amine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 2-naphthylmagnesium bromide, thetitle compound was obtained. LC/MS: (PS-A2) R_(t) 2.26 [M+H]⁺ 342. ¹HNMR (Me-d₃-OD) δ 2.57-2.70 (2H, m), 2.70 (3H, s), 2.90-3.10 (2H, m),4.32 (1H, t), 7.40-7.52 (5H, m), 7.70 (2H, m), 7.80-7.90 (4H, m), 8.70(2H, s).

Example 53Dimethyl-(4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenyl)-amine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-(N,N-dimethyl)anilinemagnesiumbromide, the title compound was obtained. LC/MS: (PS-A2) R_(t) 1.55[M+H]⁺ 335. ¹H NMR (Me-d₃-OD) δ 2.46-2.60 (2H, m), 2.69 (3H, s), 2.95(2H, t), 3.27 (6H, s), 4.25 (1H, t), 7.45 (2H, d), 7.60-7.72 (6H, m),8.50 (2H, s).

Example 54{3-(4-Fluoro-phenyl)-3-[4-(1H-pyrazol-4-1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-fluorophenylmagnesium bromide, thetitle compound was obtained. LC/MS: (PS-A2) R_(t) 2.05 [M+H]⁺ 310. ¹HNMR (Me-d₃-OD) δ 2.40-2.55 (2H, d), 2.70 (3H, s), 2.90-3.0 (2H, m), 4.12(1H, t), 7.05 (2H, t), 7.32-7.40 (4H, m), 7.63 (2H, d), 8.33 (2H, s).

Example 554-{4-[4-(4-Chloro-phenyl)-piperidin-4-yl]-phenyl}-1H-pyrazole-3-carbonitrile

Following the procedure of Example 1 but using4-(4-Chloro-phenyl)-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidineinstead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand 4-bromo-1H-pyrazole-3-carbonitrile instead of2-(4-chlorophenyl)-2-phenylethylamine hydrochloride gave the titlecompound. LC/MS: (PS-A2) R_(t) 2.22 [M+H]⁺ 363. ¹H NMR (Me-d₃-OD) δ2.52-2.70 (4H, m), 3.10-3.20 (4H, m), 7.25 (4H, s), 7.37 (2H, d), 7.58(2H, d), 8.02 (1H, s).

Example 563-(4-Phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-phenoxyphenylmagnesium bromide andmethylamine for ammonia the title compound was obtained. LC/MS: (PS-A2)R_(t) 2.28 [M+H]⁺ 370.34. ¹H NMR (Me-d₃-OD) δ 2.38-2.46 (2H, m),2.85-2.92 (2H, t), 4.03-4.10 (1H, t), 6.94-7.0 (4H, d), 7.08-7.14 (1H,t), 7.30-7.39 (6H, m), 7.55-7.58 (2H, d), 7.90-7.97 (2H, br s),8.54-8.60 (1H, br s).

Example 571-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for1-(4,4′-dichloro-benzhydryl)-piperazine gave the title compound. LC/MS:(PS-B3) R_(t) 2.82 [M−H]⁺ 351.27. ¹H NMR (Me-d₃-OD) δ 3.0-3.25 (4H, m),3.45-3.65 (4H, m), 5.05-5.25 (1H, br s), 7.40-7.50 (2H, d), 7.65-7.83(6H, m), 8.45 (2H, s).

Example 581-Methyl-4-{phenyl-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-[1,4]diazepane

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for1-[p-chlorodiphenylmethyl]-4-methyl-1,4-diazacycloheptanedihydrochloride gave the title compound. LC/MS: (PS-B3) R_(t) 2.85[M+H]⁺ 347.18. ¹H NMR (Me-d₃-OD) δ 2.25-2.60 (2H, br m), 3.00 (3H, s),3.40-4.18 (8H, br m), 5.78 (1H, s), 7.40-7.48 (1H, m), 7.49-7.55 (2H,t), 7.75-7.80 (2H, d), 7.82-7.98 (4H, m), 8.32 (2H, s).

Example 59{3-(3-Chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine59A. 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol

-   (J. Med. Chem, 2004, 47, 3924-3926)

To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1 g, 4.04mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodiumborohydride (0.16 g, 4.28 mmol). The reaction mixture was stirred atroom temperature for 2 hours, quenched with careful addition of waterand extracted with ethyl acetate. The organic layers were separated,dried (MgSO₄), filtered and concentrated to afford the title compound,which was used in the next step without further purification. LC/MS.(PS-A2) R_(t) 3.07 [M+H]⁺ No Ionization.

59B. [3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-chloride

3-Chlorophenol was reacted with 1-(4-Bromo-phenyl)-3-chloro-propan-1-olfollowing the procedure set out in Example 48B to give the titlecompound, which was used in the next step without further purification.

59C. [3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-methyl-amine

A solution of 3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-chloridein 33% methylamine in ethanol (4 ml) was heated in a CEM microwave at100° C. for 30 minutes using 50 W power. Solvent was removed and thecrude product was purified over Phenomenex_Strata_SCX ion exchangecolumn eluting with methanol followed by 2N ammonia in methanol. Theproduct was purified by column chromatography (SiO₂), eluting withdichloromethane to dichloromethane:methanol:acetic acid:water(90:18:3:2) using the SP4 biotage to afford the title compound. LC/MS:(PS-B3) R_(t) 3.42 [M+H]⁺ 356.19.

59D.{3-(3-Chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

[3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-methyl-amine wasreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-B3) R_(t) 2.80 [M+H]⁺ 342.26. ¹H NMR (Me-d₃-OD) δ 2.19-2.30(1H, m), 2.30-2.45 (1H, m), 2.72 (3H, s), 3.10-3.28 (2H, m), 5.40-5.47(1H, m), 6.80-6.88 (1H, d), 6.88-6.94 (1H, d), 6.96 (1H, s), 7.15-7.20(1H, t), 7.38-7.45 (2H, d), 7.57-7.65 (2H, d), 7.98 (2H, s).

Example 60Methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine 60A.6-(3-Methyl-1-trityl-1H-pyrazol-4-yl)-nicotinonitrile

To a solution of 6-Chloro-nicotinonitrile (0.2 g, 1.49 mmol) and3-methyl-1-trityl-1H-pyrazole-4-boronic acid* (0.5 g, 1.36 mmol) inethylene glycol dimethyl ether (3 ml), was added sodium carbonate (0.36g, 3.39 mmol) in water (1.5 ml). The reaction mixture was degassed withnitrogen before addition of tetrakis(triphenylphosphine)palladium (0)and then heated in a CEM microwave at 135° C. for 30 minutes (50 Wpower). Reaction partitioned between water and ethyl acetate, aqueousbasified with 2N NaOH, organic extracts were combined, dried (MgSO₄) andsolvent removed. Crude product suspended in small volume of methanol,white precipitate filtered to afford the title compound (0.32 g, 53%yield). LC/MS: (PS-A2) R_(t) 4.52 [M+H]⁺ 427.26. * This startingmaterial can be made by the method described in EP1382603A1

60B.(4-Chloro-phenyl)-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone

To a solution of 6-(3-Methyl-1-trityl-1H-pyrazol-4-yl)-nicotinonitrile(0.5 g, 1.17 mmol) in dry tetrahydrofuran (4 ml) was added4-chlorobenzenemagnesium bromide (1.52 ml, 1.52 mmol, 1M in diethylether); the reaction mixture was stirred under nitrogen for 16 hours.The reaction was quenched to below pH 2 by the addition of 2N HCl andstirred for 1 hour. Then adjusted to pH 8 with saturated sodiumbicarbonate and extracted with ethyl acetate. Organic extracts werecombined, dried (MgSO₄), solvent removed and residue purified by columnchromatography (SiO₂), eluting with petrol to ethyl acetate: petroleumether (15:85) to yield the title compound (0.49 mg, 77% yield). LC/MS:(PS-A2) R_(t) 4.45 [M+H]⁺ 540.30, 542.28.

60C.{2-(4-Chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-vinyl}-methyl-(1-phenyl-ethyl)-amine

n-Butyllithium (0.47 ml, 0.76 mmol, 1.6M in Hexanes) was added dropwiseto a solution of (R)(Diphenyl-phosphinoylmethyl)-methyl-(1-phenyl-ethyl)-amine* (0.18 g,0.51 mmol) in dry tetrahydrofuran (9 ml) at −15° C. After 15 minutes asolution of(4-Chloro-phenyl)-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone(0.14 g, 0.25 mmol) in tetrahydrofuran (0.9 ml) was added and thereaction mixture was stirred for a further 30 minutes at −15° C. beforewarming to room temperature over 1 hour. The reaction mixture wasquenched with water, extracted with diethyl ether, organic extracts werecombined, dried (MgSO₄) and concentrated to afford the title compound,which was used in the next step without further purification. * Thisstarting material can be made by the method described in TetrahedronAsymmetry, 2003, 14, 1309-1316.

60D. Methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine

To a solution of{2-(4-Chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-vinyl}-methyl-(1-phenyl-ethyl)-aminein ethanol was added palladium, 10 wt. % on activated carbon and thereaction mixture was subjected to a hydrogen atmosphere for 17 hours.The mixture was filtered through Celite®, the mother liquor wasconcentrated, the residue was purified by column chromatography (SiO₂),eluting with dichloromethane: methanol: acetic acid: water (240:20:3:2)to dichloromethane: methanol: acetic acid: water (90:18:3:2) to affordthe title compound. LC/MS: (PS-A2) R_(t) 1.59 [M+H]⁺ 293.18. ¹H NMR(Me-d₃-OD) δ 2.35 (3H, s), 2.40 (3H, s), 3.25 (2H, s), 4.15-4.20 (1H,t), 7.10-7.18 (1H, m), 7.25 (4H, m), 7.45 (1H, d), 7.67 (1H, dd), 7.80(1H, s), 8.38 (1H, s).

Example 614-{4-[1-(4-Chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1H-pyrazole61A. 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol

A solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml)was heated at 100° C. for 18 hrs then partitioned between water andethyl acetate. The organic extracts were combined, dried (MgSO₄),filtered, concentrated and purified by column chromatography (SiO₂),eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane(6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3)R_(t) 2.48 [M+H]⁺ 281.14, 283.11. *This starting material can be made bythe method described in Example 43A.

61B. 1-[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-1H-imidazole

Chlorobenzene (5 ml) was reacted with1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol (0.41 mg, 1.46 mmol)following the procedure set out in Example 42B to give the titlecompound (0.37 g, 67% yield). LC/MS: (PS-A2) R_(t) 2.40 [M+H]⁺ 375.16,377.17.

61C.4-{4-[1-(4-Chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1H-pyrazole

1-[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-1H-imidazole wasreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-A2) R_(t) 2.21 [M+H]⁺ 363.28. ¹H NMR (Me-d₃-OD) δ 2.55-2.70(2H, m), 3.85-3.95 (1H, m), 3.95-4.10 (2H, m), 7.05 (1H, s), 7.10-7.60(9H, m), 7.65 (1H, s), 7.90-8.00 (2H, d).

Example 62 4-[4-(3-Imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1H-pyrazole62A. 1-[3-(4-Bromo-phenyl)-3-phenoxy-propyl]-1H-imidazole

Phenol was reacted with 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol*following the procedure set out in Example 48B to give the titlecompound. LC/MS: (PS-A2) R_(t) 2.30 [M+H]⁺ 357.26, 359.27. *Thisstarting material can be made by the method described in Example 47A.

62B. 4-[4-(3-Imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1H-pyrazole

1-[3-(4-Bromo-phenyl)-3-phenoxy-propyl]-1H-imidazole was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-A2) R_(t) 2.05 [M+H]⁺ 345.30. ¹H NMR (Me-d₃-OD) δ 2.30-2.55 (2H, m),4.25-4.45 (2H, m), 5.10-5.15 (1H, m), 6.80-6.90 (3H, m), 7.10 (1H, s),7.15-7.20 (2H, t), 7.25 (1H, s), 7.35-7.40 (2H, d), 7.55-7.60 (2H, d),7.85 (1H, s), 7.95 (2H, s).

Example 63 4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenol

By following the procedure described in Example 14 but substitutingchlorobenzene for phenol using nitrobenzene as the solvent, the titlecompound was obtained. LC/MS: (PS-A3) R_(t) 5.07 [M+H]⁺ 320. ¹H NMR(d₆-DMSO) δ 7.97 (2H, s), 7.49 (2H, d), 7.25 (2H, d), 7.10 (2H, d), 6.68(2H, d), 2.840 (4H, bs), 2.376 (4H, bs).

Example 641-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine

By following the procedure described in Example 57, the title compoundwas obtained. LCMS: (PS-A3) R_(t) 6.38 [M+H]⁺ 319. ¹H NMR (Me-d₃-OD) δ8.53 (2H, s), 7.90 (2H, d), 7.83 (2H, d), 7.71 (2H, d), 7.40-7.30 (3H,m), 5.70 (1H, s), 3.68 (4H, bs), 3.51-3.48 (4H, m).

Example 65{2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine65A. [2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzylester

To a solution of 3-(4-fluorophenyl)-3-(4-bromophenyl)propionic acid*(1.0 g, 3.09 mmol) in acetone (4 ml) at 0° C. was sequentially addedtriethylamine (561 ul, 4.02 mmol) in acetone (1.6 ml) and ethylchloroformate (443 ul, 4.64 mmol) in acetone (1.6 ml). The reaction wasallowed to warm to room temperature, stirred for 30 minutes beforecooling again to 0° C. and sodium azide (402 mg, 6.18 mmol) in water(1.6 ml) was added. The resultant brown solution was stirred for 45minutes before addition of water (10 ml) and diethyl ether (10 ml). Theaqueous layer was separated and extracted further with ethyl acetate (10ml). The combined organic liquors were washed with saturated brine,dried (MgSO₄) and concentrating in vacuo. The residue was dissolved inanhydrous toluene (12 ml) before addition of benzyl alcohol (567 ul,9.27 mmol) and heating to 80° C. for 40 minutes. The reaction wasallowed to cool to room temperature before addition of ethyl acetate (50ml) and saturated sodium bicarbonate (50 ml). The organic liquors wereseparated and washed with further bicarbonate solution (50 ml),hydrochloric acid (2N, 100 ml) and saturated brine (50 ml) before drying(MgSO₄) and concentrating in vacuo. The residue was purified by columnchromatography (SiO₂), eluting with ethyl acetate/petrol (5:95) gradientto (15:85) to afford the title compound (594 mg, 45%). LC/MS: (PS-A2)R_(t) 3.18 No Ionisation. * This starting material can be made by themethod described in Example 8A to 8C, substituting4-chlorophenylmagnesium bromide for 4-fluorophenylmagnesium bromide

65B. {2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-carbamicacid benzyl ester

[2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzylester was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-A2) R_(t) 3.20 [M+H]⁺ 416.

65C.{2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

Lithium aluminium hydride (5.3 ml, 5.30 mmol, 1M in tetrahydrofuran) wasslowly added to{2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-carbamic acidbenzyl ester (439 mg, 1.06 mmol) in tetrahydrofuran (5 ml) at 0° C.under nitrogen. The reaction mixture was allowed to warm to roomtemperature, stirred for 51 hours and quenched with water (5 ml),aqueous sodium hydroxide (2N, 5 ml) and ethyl acetate (10 ml). Theaqueous layer was separated, extracted with ethyl acetate (2×20 ml). Thecombined organic liquors were washed with saturated aqueous brine thendried (MgSO₄) and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂), eluting withdichloromethane:methanol:acetic acid:water (120:15:3:2) gradient to(90:18:3:2) to afford the title compound, which was subsequentlyconverted to the hydrochloride salt (100 mg, 32%). LC/MS: (PS-A2) R_(t)1.87 [M+H]⁺ 296. ¹H NMR (Me-d₃-OD) δ 8.20 (2H, s), 7.57 (2H, d),7.34-7.29 (4H, m), 7.02 (2H, t), t), 4.32 (1H, t), 3.67 (2H, d), 2.65(3H, s).

Example 66{2-(3-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 65 but substituting4-fluorophenylmagnesium bromide for 3-chlorophenylmagnesium bromide thetitle compound was obtained. LC/MS: (PS-A3) R_(t) 4.92 [M+H]⁺ 312. ¹HNMR (Me-d₃-OD) δ 8.50 (2H, s), 7.63 (2H, d), 7.39 (2H, d), 7.34 (1H, s),7.30-7.20 (3H, m), 4.40 (1H, t), 3.70 (2H, d), 2.65 (3H, s).

Example 674-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine67A. 4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

By following the procedure described in Example 47B but substituting4-[1-(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol for4-[4-(4-Bromo-phenyl)-piperidin-4-yl]-phenol* the title compound wasobtained. ¹H NMR (d₆-DMSO) δ 7.45 (2H, d), 7.25 (2H, d), 7.11 (2H, d),6.68 (2H, d), 3.35-3.18 (4H, m), 2.31-2.20 (4H, m), 1.38 (9H, s). * Thisstarting material can be made by the method described in Example 63

67B.4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

A solution of4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (100 mg, 0.23 mmol), 2-bromoethyl methylether (200 ul)and potassium carbonate (64 mg, 0.46 mmol) in dimethylformamide (2 ml)was heated in a CEM Explorer™ microwave to 50° C. for 30 minutes using50 watts power. The reaction was poured into sodium hydroxide (2N, 4ml), stirred for 5 minutes then extracted into ethyl acetate (2×30 ml).The combined organic liquors were dried (MgSO₄), concentrated and theresidue was purified by column chromatography (SiO₂), eluting with ethylacetate/petrol (25:75) gradient to (50:50) to afford the title compound(82 mg). LCMS: (PS-A2) R_(t) 4.00 [M+H]⁺ 490.

67C.4-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1H-pyrazole followingthe procedure set out in Example 1, substituting tetrakistriphenylphosphine palladium (0) as catalyst, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 3.27 [M+H]⁺ 478.

67D.4-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

Trifluoroacetic acid (1 ml) was added to a solution of4-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine(87 mg) in dichloromethane (1 ml). After 30 minutes at room temperature,the reaction was concentrated. The residue was dissolved methyl acetatethen extracted into hydrochloric acid (2N, 2×20 ml). The combinedaqueous fractions were washed with ethyl acetate then basified (2N NaOH)before back-extraction into ethyl acetate (2×20 ml). The combinedorganic liquors were washed with saturated brine solution then dried(MgSO₄) and concentrated to yield the title compound (66 mg). LCMS:(PS-A3) R_(t) 6.08 [M+H]⁺ 378. ¹H NMR (Me-d₃-OD) δ 7.92 (2H, s), 7.51(2H, d), 7.31 (2H, d), 7.25 (2H, d), 6.89 (2H, d), 4.13 (2H, t), 3.73(2H, t), 3.42 (3H, s), 2.94 (4H, bs), 2.44 (4H, bs).

Example 684-[4-(3-Methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine68A.4-(4-Bromo-phenyl)-4-[4-(3-methoxy-propoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

Tosyl chloride (572 mg, 3.0 mmol) was added to a solution of3-methoxypropanol (191 ul, 2.0 mmol) in pyridine (1 ml). This wasstirred at room temperature for 5.5 hours then diluted with ethylacetate (20 ml) and washed with hydrochloric acid (2N, 3×10 ml) andsaturated brine (10 ml). The liquors were dried (MgSO₄) and concentratedto furnish a colourless oil (600 mg). This oil was dissolved indimethylformamide (2 ml) and to this solution was added potassiumcarbonate (64 mg, 0.46 mmol) and4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acidtert-butyl ester* (100 mg, 0.231 mmol). The resultant mixture wasstirred at 100° C. for 4 hours. Once cooled, water (20 ml) was added andthe mixture was extracted with ethyl acetate (3×10 ml). The combinedorganic liquors were washed with brine (10 ml) before drying (MgSO₄) andconcentrating. The residue was purified by column chromatography (SiO₂),eluting with a gradient from 10-20% ethyl acetate/petrol to furnish thetitle compound as a colourless oil (131 mg). LCMS: R_(t) 4.20 [M+H]⁺504. * This starting material can be made by the method described inExample 67A

68B.4-[4-(3-Methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 67C and 67D butsubstituting4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester for4-(4-Bromo-phenyl)-4-[4-(3-methoxy-propoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester the title compound was obtained. LCMS: R_(t) 6.65[M+H]⁺ 392. ¹H NMR (Me-d₃-OD) δ 7.94 (2H, s), 7.57 (2H, d), 7.34 (2H,d), 7.27 (2H, d), 6.91 (2H, d), 4.04 (2H, t), 3.56 (2H, t), 3.34-3.33(5H, m), 3.24-3.22 (4H, m), 2.67-2.66 (4H, m)

Example 693-(3,4-Dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide

By following the procedure described in Example 9A and 9B butsubstituting 3,4-difluorophenylmagnesium bromide for3,4-dichlorophenylmagnesium bromide, the title compound was obtained.LC/MS: (PS-A3) R_(t) 9.82 [M+H]⁺ 360.14, 362.12. ¹H NMR (Me-d₃-OD) δ2.90-3.00 (2H, d), 4.50-4.60 (1H, t), 7.10-7.30 (3H, m), 7.40-7.45 (2H,d), 7.50-7.55 (2H, d), 7.85-8.05 (2H, br s).

Example 702-(4-{2-Methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamide

By following the procedure described in Example 47, but substituting2-chloropyrazine for 2-chloro-4-cyanopyridine, the title compound wasobtained. LC/MS. (PS-B3) R_(t) 2.27 [M+H]⁺ 414. ¹H NMR (Me-d₃-OD) δ 2.45(3H, s), 3.55 (1H, dd), 3.65 (1H, dd), 4.25 (1H, t), 7.10 (2H, d),7.30-7.38 (3H, m), 7.40 (2H, d), 7.48 (1H, d), 7.56 (2H, d), 7.95 (2H,s), 8.22 (1H, d).

Example 71{2-(4-Chloro-phenoxy)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 48, but substitutingphenol for 4-chlorophenol, the title compound was obtained. LC/MS:(PS-A3) R_(t) 2.29 [M−ClPhO+H]⁺ 200. ¹H NMR (Me-d₃-OD) δ 2.50 (3H, s),2.86 (1H, dd), 3.10 (1H, dd), 5.35 (1H, dd), 6.89 (2H, d), 7.17 (2H, d),7.40 (2H, d), 7.57 (2H, d), 7.93 (2H, s).

Example 723-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol

By following the procedure described in Example 20 but substitutingdimethylamine for 3-aminopropan-1-ol the title compound was obtained.LC/MS: (PS-A2) R_(t) 2.05 [M+H]⁺ 356. ¹H NMR (Me-d₃-OD) δ 1.87 (2H,quintet), 1.98 (AcOH, s), 3.23 (2H, t), 3.68 (2H, t), 3.75 (2H, dd), 4.4(1H, t), 7.36 (2H, d), 7.4 (4H, s), 7.62 (2H, d), 7.97 (2H, s).

Example 732-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol

By following the procedure described in Example 20 but substitutingdimethylamine for 2-aminoethan-1-ol the title compound was obtained.LC/MS: (PS-A2) R_(t) 2.05 [M+H]⁺ 342. ¹H NMR (Me-d₃-OD) δ 1.98 (AcOH,s), 3.10 (2H, s), 3.69 (2H, dd), 3.78, (2H, t), 4.39 (1H, t), 7.36 (2H,d), 7.38 (4H, s), 7.61 (2H, d), 7.97 (2H, s).

Example 74{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethyl-amine

By following the procedure described in Example 20 but substitutingdimethylamine for cyclopropylmethylamine the title compound wasobtained. LC/MS: (PS-A2) R_(t) 2.21 [M+H]⁺ 352. ¹H NMR (Me-d₃-OD) δ−0.4-0.3 (2H, m), 0.35-0.40 (2H, m), 0.78-0.87 (1H, m), 2.42 (2H, d),3.15-3.25 (2H, m), 4.11 (1H, t), 7.16-7.27 (6H, m), 7.45 (2H, d), 7.82,(2H, s).

Example 75Methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-amine

By following the procedure described in Example 1 but substituting4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and couplingto{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine*,the title compound was obtained. LC/MS: (PS-B3) R_(t) 2.42 [M+H]⁺ 355.¹H NMR (Me-d₃-OD) δ 1.94 (AcOH, s), 2.72 (3H, s), 3.73 (2H, d), 4.46(1H, t), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d),7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d). * Thisstarting material can be made by the method described in Example 21.

Example 764-{3-Methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-anisylmagnesium bromide, the titlecompound can be obtained LC/MS: (PS-A2) R_(t) 1.82 [M+H]⁺ 308. ¹H NMR(Me-d₃-OD) δ 1.92 (AcOH, s), 2.34-2.43 (2H, m), 2.64 (3H, s), 2.86-2.92(2H, m), 3.96 (1H, t), 6.75 (2H, d), 7.13 (2H, d), 7.29 (2H, d), 7.52(2H, d), 7.93 (2H, d).

Example 773-(4-Methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-anisylmagnesium bromide andmethylamine for ammonia (2M in methanol), the title compound wasobtained. LC/MS: (PS-A2) R_(t) 1.82 [M+H]⁺ 308. ¹H NMR (Me-d₃-OD) δ2.23-2.32 (2H, m), 2.74 (2H, dd), 3.65 (3H, s), 3.89 (1H, t), 6.77 (2H,d), 7.11 (2H, s), 7.17 (2H, d), 7.41 (2H, d), 7.71 (2H, s), 8.41 (HCO₂H,br s).

Example 784-(4-Chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidine78A.4-(4-Chloro-phenyl)-4-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine hydrochloride wasreacted with 3-methyl-1-trityl-1H-pyrazole-4-boronic acid* following theprocedure set out in Example 1, but using tetrakis(triphenylphosphine)palladium (0) as the catalyst to give the title compound. LC/MS: (PS-B3)R_(t) 2.78 min [M+H]⁺ 594. * This starting material can be made by themethod described in EP1382603

78B.4-(4-Chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidine

A suspension of4-(4-chloro-phenyl)-4-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-piperidine(178 mg, 0.30 mmol) in 5N hydrochloric acid (5 mL), THF (5 mL) andmethanol (5 mL) was stirred for 140 minutes. The organic solvents wereremoved in vacuo then the resulting solution was diluted with 2N HCl andwashed with ether. The aqueous phase was basified by addition of sodiumhydroxide pellets then extracted with ethyl acetate. This organicextract was washed with brine, dried (MgSO₄), filtered and concentratedto give a residue which was purified by column chromatography (SiO₂),eluting with a gradient of 2M ammonia in methanol (5% to 7.5%) anddichloromethane. The product was further purified by preparative HPLC togive the title compound which was converted to its dihydrochloride salt(84 mg, 80%); LCMS (PS-A3) R_(t) 6.86 min [M+H]⁺ 352. ¹H NMR (Me-d₃-OD)δ 2.55 (3H, s), 2.70-2.75 (4H, m), 3.22-3.27 (4H, m), 7.35-7.41 (4H, m),7.47-7.54 (4H, m), 8.32 (2H, s).

Example 79 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine79A. 2-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-oxirane

Sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol) was placedunder N₂ then DMSO (5 mL) was added. Trimethylsulfonium iodide (0.66 g,3.2 mmol) was added as a solid after 15 min, followed after a further 30min by (4-chloro-phenyl)-(4-iodo-phenyl)-methanone. The mixture wasstirred at room temperature for 24 hours then diluted with ethyl acetateand washed with 1:2 water/brine, water and brine (×2). The organic phasewas dried (MgSO₄), filtered and concentrated to give the title compound(1.01 g, 97%), which was used without further purification. LCMS (PS-A2)R_(t) 4.07 min [M−H]⁻ 355.

79B.1-(4-Chloro-phenyl)-2-(2-hydroxy-ethylamino)-1-(4-iodo-phenyl)-ethanol

A solution of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane (0.60 g,1.68 mmol), ethanolamine (0.5 mL, 8.3 mmol) and triethylamine (0.5 mL,3.6 mmol) in isopropanol (5 mL) was maintained at 50° C. for 72 hoursthen concentrated in vacuo. The residue was taken up in ethyl acetateand washed with saturated potassium carbonate solution/water (1:9). Theaqueous phase was extracted a second time with ethyl acetate, then thecombined extracts were washed with brine, dried (MgSO₄), filtered andconcentrated to give the title compound (701 mg, quantitative); LCMS(PS-A2) R_(t) 2.29 min [M+H]⁺ 418, [M−H₂O+H]⁺ 400.

79C. 2-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-morpholine

A solution of1-(4-chloro-phenyl)-2-(2-hydroxy-ethylamino)-1-(4-iodo-phenyl)-ethanol(701 mg, 1.68 mmol) in DCM (10 mL) was treated with concentrated H₂SO₄(0.1 mL, 1.9 mmol). After 20 hours, another portion of H₂SO₄ (1.0 mL, 19mmol) was added and the mixture stirred for a further 2 hours. Themixture was diluted with ethyl acetate and washed with saturatedpotassium carbonate and brine then dried (MgSO₄), filtered andconcentrated. The residue was purified by column chromatography (SiO₂),eluting with 0.5% triethylamine in ethyl acetate to afford the titlecompound (290 mg, 43%); LCMS (PS-A2) R_(t) 2.40 min [M+H]⁺ 400.

79D. 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine

2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-morpholine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, but usingtetrakis(triphenylphosphine) palladium (0) as the catalyst to give thetitle compound. LCMS (PS-A3) R_(t) 6.88 min [M+H]⁺ 340. ¹H NMR(Me-d₃-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m),3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d),7.92 (2H, br. s).

Example 80(4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acidand (4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-aceticacid, methyl ester

80A. {4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethylester

By following the procedure described in Example 42B but substitutingchlorobenzene for ethyl phenoxyacetate and employing nitrobenzene assolvent, the title compound was obtained. LCMS (PS-A2) R_(t) 2.37 min[M+H]⁺ 418.

80B. (4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-aceticacid and(4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid,methyl ester

{4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethyl esterwas reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, but usingtetrakis(triphenylphosphine) palladium (0) as the catalyst and heatingat 80° C. for 30 minutes, to yield a mixture of the title compounds. Onwork up the basic aqueous extract was neutralised with hydrochloric acidand extracted with ethyl acetate (×2), then these organic extracts werecombined and washed with brine, dried (MgSO₄), filtered and concentratedto give a crude product that was recrystallised from water to afford(4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid(12 mg, 5%); LCMS (PS-A3) R_(t) 5.33 min [M+H]⁺ 378. ¹H NMR (DMSO-d₆) δ2.22-2.26 (4H, m), 2.67-2.71 (4H, m), 4.65 (2H, s) 6.67 (2H, d), 7.11(2H, d), 7.24 (2H, d), 7.46 (2H, d), 7.96 (2H, br. s).

The material which was not extracted into base was converted on standingin methanol to a single compound,{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid,methyl ester. This was purified by preparative HPLC to afford the titlecompound (18 mg, 7%); LCMS (PS-A3) R_(t) 6.13 min [M+H]⁺ 392. ¹H NMR(Me-d₃-OD) δ 2.34-2.45 (4H, m), 2.87 (4H, apparent t), 3.75 (3H, s),6.83 (2H, d), 7.21 (2H, d), 7.26 (2H, d), 7.47 (2H, d), 7.89 (2H, s).

Example 814-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile 81A.4-(4-Chloro-phenyl)-4-(4-iodo-phenyl)-piperidine

By following the procedure described in Example 42B but substitutingchlorobenzene for iodobenzene, the title compound was obtained. LCMS(PS-A2) 2.68 min [M+H]⁺ 398.

81B. 4-[4-(4-Chloro-phenyl)-piperidin-4-yl]-benzonitrile

A mixture of 4-(4-chloro-phenyl)-4-(4-iodo-phenyl)-piperidine and copper(I) cyanide in DMF was heated at 140° C. under nitrogen for 6 hours thenallowed to cool. The mixture was diluted with ethyl acetate, washed witha mixture of conc. ammonia and brine (×5), dried (MgSO₄), filtered andconcentrated to give a residue which was partially purified by columnchromatography (SiO₂), eluting with a gradient of 2M ammonia in methanol(5% to 10%) and dichloromethane to afford the title compound (46 mg,<16%). This was taken on to the next reaction without furtherpurification. LCMS (PS-A2) R_(t) 2.39 min [M+H]⁺ 297.

81C. 4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile

4-[4-(4-chloro-phenyl)-piperidin-4-yl]-benzonitrile was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, but usingtetrakis(triphenylphosphine) palladium (0) as the catalyst and heatingat 100° C. for 15 minutes, to obtain the title compound. LCMS (PS-A3)R_(t) 6.68 min [M+H]⁺ 329. ¹H NMR (Me-d₃-OD) δ 2.65-2.73 (4H, m),2.77-2.85 (4H, m), 3.75 (3H, s), 7.46 (2H, d), 7.59 (2H, d), 7.68 (2H,d), 7.71 (2H, d), 8.42 (2H, br. s).

Example 82{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine82A. Bis-(4-chloro-phenyl)-acetic acid methyl ester

Bis-(4-chloro-phenyl)-acetic acid (4.33 g, 15.4 mmol) was suspended inanhydrous methanol (20 mL) and concentrated hydrochloric acid (5 drops)was added. After 1 day the reaction was quenched by the addition ofsaturated sodium bicarbonate solution, then the organic solvent wasremoved in vacuo. The residue was partitioned between ethyl acetate and50% saturated potassium carbonate solution. The organic phase was washedwith brine, dried (MgSO₄), filtered and concentrated to give a residuewhich was purified by column chromatography (SiO₂), eluting with 10%ethyl acetate/petrol, to afford the title compound as a colourless oil(3.57 g, 78%); LCMS (PS-B3) R_(t) 3.79 min, No Ionisation. ¹H NMR(CDCl₃) δ 3.74 (3H, s), 4.96 (1H, s), 7.20-7.23 (4H, m), 7.28-7.32 (4H,m).

82B. 2,2-Bis-(4-chloro-phenyl)-propionic acid methyl ester

A solution of bis-(4-chloro-phenyl)-acetic acid methyl ester (1.19 g,4.0 mmol) in THF (20 ml) was cooled to −78° C. under nitrogen. Asolution of LDA (3.0 mL, 6.0 mmol, 2M in heptane/THF/ethylbenzene) wasadded over 5 minutes, then after a further 20 minutes, iodomethane (0.63ml, 10.1 mmol) was added. After 4 hours the reaction was quenched by theaddition of saturated ammonium chloride solution and allowed to warm toroom temperature then concentrated in vacuo to remove organic solvents.The mixture was diluted with ethyl acetate/petrol 1:4 and washed withsaturated ammonium chloride solution then brine, dried (MgSO₄), filteredand concentrated to give a residue which was purified by columnchromatography (SiO₂), eluting with an ethyl acetate/petrol gradient (1%to 2%), to afford the title compound as a colourless oil (210 mg, 17%);LCMS (PS-B3) R_(t) 4.01 min, No Ionisation. ¹H NMR (CDCl₃) δ 1.88 (3H,s), 3.73 (3H, s), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).

82C. 2,2-Bis-(4-chloro-phenyl)-propionic acid

A solution of 2,2-bis-(4-chloro-phenyl)-propionic acid methyl ester (210mg, 0.67 mmol) in THF/water/methanol (1:1:1, 18 mL) was stirred at roomtemperature for 5 days then concentrated in vacuo. The residue waspartitioned between ethyl acetate and 2N hydrochloric acid, then theorganic phase was washed with brine, dried (MgSO₄), filtered andconcentrated to give the title compound (186 mg, 93%) as a yellow solidwhich was used without further purification. LCMS (PS-B3) R_(t) 2.40 min[M−CO₂H]⁻ 249.

82D. 2,2-Bis-(4-chloro-phenyl)-N-methyl-propionamide

By following the procedure described in Example 8D but substituting3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid for2,2-bis-(4-chloro-phenyl)-propionic acid, the title compound wasobtained. LCMS (PS-B3) R_(t) 3.40 min [M+H]⁺ 308.

82E. [2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine

By following the procedure described in Example 8E but substituting3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide for2,2-Bis-(4-chloro-phenyl)-N-methyl-propionamide, the title compound wasobtained. LCMS (FL-A) R_(t) 2.35 min [M+H]⁺ 294

82F.{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

[2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LCMS(PS-A3) R_(t) 6.94 min [M+H]⁺ 326. ¹H NMR (Me-d₃-OD) δ 1.86 (3H, s),2.77 (3H, s), 3.89 (2H, s), 7.26-7.33 (4H, m), 7.37-7.40 (2H, m), 7.68(2H, d), 8.35 (2H, s).

Example 831-(4-Chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

By following the procedure described in Example 79A, 79B and 79D butsubstituting ethanolamine for methylamine, the title compound wasobtained. LCMS (PS-A3) R_(t) 5.28 min [M+H]⁺ 328, [M−H₂O+H]⁺ 310. ¹H NMR(Me-d₃-OD) δ 2.38 (3H, s), 3.34 (2H, s), 7.28-7.31 (2H, m), 7.41-7.46(4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s).

Example 842-Amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol 84A.2-[2-(4-Chloro-phenyl)-2-hydroxy-2-(4-iodo-phenyl)-ethyl]-isoindole-1,3-dione

A mixture of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane* (571 mg,1.60 mmol) and potassium phthalimide (340 mg, 1.84 mmol) in THF (5 mL)and DMSO (2 mL) was heated at 100° C. for 20 hours. The mixture wasconcentrated in vacuo, diluted with ethyl acetate and washed with waterand brine (×2), dried (MgSO₄), filtered and concentrated to give a crudeproduct which was purified by column chromatography (SiO₂), eluting witha gradient of ethyl acetate/petrol (2.5% to 100%) then 10%methanol/dichloromethane to give the title compound (273 mg, 34%); LCMS(PS-A2) R_(t) 3.22 min [M+H]⁺ 504. * This starting material can be madeby the method described in Example 79A

84B.N-{2-(4-Chloro-phenyl)-2-hydroxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phthalamicacid

2-[2-(4-Chloro-phenyl)-2-hydroxy-2-(4-iodo-phenyl)-ethyl]-isoindole-1,3-dionewas reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, but usingtetrakis(triphenylphosphine) palladium (0) as the catalyst, to obtainthe title compound. LCMS (PS-A2) R_(t) 2.62 min [M−H]⁻ 460.

84C. 2-Amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

By following the procedure described in Example 49D but substitutingN-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-phthalamicacid forN-{2-(4-Chloro-phenyl)-2-hydroxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phthalamicacid, the title compound was obtained. LCMS (PS-A3) R_(t) 6.29 min[M−H₂O+H]⁺ 296. ¹H NMR (Me-d₃-OD) δ 3.29-3.38 (2H, m), 7.32 (2H, d),7.41-7.46 (4H, m), 7.55 (2H, d), 7.94 (2H, s).

Example 854-(3,4-Dichloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 14 but substitutingchlorobenzene for 1,2-dichlorobenzene, the title compound was obtained.LCMS (PS-B4) R_(t) 7.20 min [M+H]⁺ 372. ¹H NMR (Me-d₃-OD) δ 2.62-2.69(2H, m), 2.73-2.81 (2H, m), 3.18-3.30 (4H, m), 7.34 (1H, dd), 7.46-7.52(3H, m), 7.53 (1H, d), 7.72 (2H, d), 8.56 (2H, s).

Example 864-(3-Chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 14 but substitutingchlorobenzene for 2-chloroanisole, the title compound was obtained. LCMS(PS-B4) R_(t) 6.24 min [M+H]⁺ 368. ¹H NMR (Me-d₃-OD) δ 2.62-2.75 (4H,m), 3.23 (4H, apparent t), 3.86 (3H, s), 7.06 (1H, d), 7.30 (1H, dd),7.34 (1H, d), 7.45 (2H, d), 7.69 (2H, d), 8.57 (2H, s).

Example 874-(4-Chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine87A. 4-(4-Chloro-3-fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acidtert-butyl ester

A solution of 4-chloro-3-fluorophenylmagnesium bromide (15 ml, 7.5 mmol,0.5M in THF) was added, under nitrogen, to 4-oxo-piperidine-1-carboxylicacid tert-butyl ester (1.02 g, 5.1 mmol). After 24 hours, saturatedammonium chloride solution was added then the organic solvent wasremoved in vacuo. The mixture was extracted with ethyl acetate, thenthis extract was washed with brine, dried (MgSO₄), filtered andconcentrated to afford a residue which was purified by columnchromatography (SiO₂), eluting with gradient of ethyl acetate/petrol (0%to 20%) to afford the title compound (511 mg, 30%). ¹H NMR (Me-d₃-OD) δ1.48 (9H, s), 1.67 (2H, br. d), 1.92 (2H, td), 3.16-3.29 (2H, m), 3.99(2H, br. d), 7.27 (1H, dd), 7.38 (1H, dd), 7.42 (1H, t).

87B. 4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine

By following the procedure described in Example 42B but substitutingchlorobenzene for bromobenzene, the title compound was obtained. LCMS(PS-A2) R_(t) 2.43 min [M+H]⁺ 368.

87C.4-(4-Chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine was reactedwith 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1, but usingtetrakis(triphenylphosphine) palladium (0) as the catalyst, to obtainthe title compound. LCMS (PS-A3) R_(t) 7.11 min [M+H]⁺ 356. ¹H NMR(Me-d₃-OD) δ 2.62-2.80 (4H, m), 3.18-3.30 (partially overlaps withsolvent, 4H, m), 7.23 (1H, t), 7.34-7.39 (1H, m), 7.22 (1H, dd), 7.30(1H, dd), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H, s).

Example 88 4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzoicacid 88A.4-(4-carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidtert-butyl ester

Under nitrogen, a solution of4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidtert-butyl ester* (888 mg, 1.97 mmol) in THF (5 mL) was cooled to −78°C. A solution of n-butyllithium (1.5 mL, 1.6M in hexanes) was addeddropwise and the mixture maintained at this temperature for 25 minutes.Carbon dioxide gas (generated from dry ice and dried by passage througha column of calcium chloride pellets) was bubbled through the anionsolution for 80 minutes then the mixture was allowed to warm to roomtemperature. The solvents were removed in vacuo then the residue waspartitioned between 1N hydrochloric acid and diethyl ether. The organicphase was separated, dried (MgSO₄), filtered and concentrated. Thecombined aqueous phases were further extracted with ethyl acetate, thisextract also being dried (MgSO₄), filtered, combined with the etherealextract and concentrated to afford4-(4-carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (889 mg); LCMS (PS-A2) R_(t) 3.52 min [M−^(t)Bu+H]⁺360. * This starting material can be made by the method described inExample 14A followed by Example 48A

88B.4-(4-Carboxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

4-(4-Carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidtert-butyl ester was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, to obtain the title compound. LCMS(PS-A2) R_(t) 2.92 min [M+H]⁺ 448.

88C. 4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzoic acid

4-(4-Carboxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (26 mg, 0.06 mmol) was dissolved in dioxane (2 mL)and 1N hydrochloric acid (2 mL). After 24 hours the mixture wasconcentrated in vacuo and triturated with diethyl ether to afford thetitle compound as the dihydrochloride salt (22 mg, 90%); LCMS (PS-A3)R_(t) 5.22 min [M+H]⁺ 348 ¹H NMR (Me-d₃-OD) δ 2.70-2.82 (4H, m), 3.26(4H, apparent t), 7.46 (2H, d), 7.51 (2H, m), 7.68 (2H, d), 8.00 (2H,d), 8.47 (2H, s).

Example 894-[4-(1H-Pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl89A.4-(4-Chloro-phenyl)-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylicacid tert-butyl ester

Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acidtert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled inice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added,followed over two minutes by sodium hexamethyldisilazide solution (10mL, 20 mmol, 2M in THF). The mixture was stirred at 0° C. for 3.5 hoursthen allowed to warm to room temperature and stirred for a further 20hours. Methanol was added then the mixture was concentrated in vacuo.The residue was taken up in ethyl acetate and washed with 1Nhydrochloric acid (×3) and brine, dried (MgSO₄), filtered andconcentrated to afford a residue which was purified by columnchromatography (SiO₂), eluting with gradient of 2M methanolic ammonia indichloromethane (1% to 5%). A second purification by columnchromatography (SiO₂), eluting with 50% ethyl acetate/petrol gave thetitle compound (16 mg, 0.7%). LCMS (PS-A2) R_(t) 2.65 min [M+H]⁺ 373. *This starting material can be made by the method described in J. Chem.Soc., Perkin Trans 1, 2000, p 3444-3450

89B.4-[4-(1H-Pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl

4-(4-Chloro-phenyl)-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylicacid tert-butyl ester was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, followed by treatment with 4M HCl indioxane, to obtain the title compound. LCMS (PS-B4) R_(t) 4.28 min[M+H]⁺ 305. ¹H NMR (Me-d₃-OD) δ 2.76 (2H, br. t), 3.01 (2H, br. d), 3.24(2H, br. t), 3.39 (2H, br. d), 7.58 (2H, d), 7.76 (2H, d), 8.17 (2H, d),8.37 (2H, s), 8.82 (2H, d).

Example 903-(3-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 3-chlorophenylmagnesium bromide andmethylamine for ammonia the title compound was obtained. LCMS (PS-B3)R_(t) 2.60 min [M+H]⁺ 312. ¹H NMR (Me-d₃-OD) δ 2.44 (2H, apparent qd),2.87 (2H, dd), 4.14 (1H, t), 7.24 (1H, dt), 7.27-7.33 (2H, m), 7.34 (1H,t), 7.42 (2H, d), 7.68 (2H, d), 8.58 (2H, s).

Example 912-Methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

By following the procedure described in Example 83 but substituting(4-chloro-phenyl)-(4-iodo-phenyl)-methanone for(4-Bromo-phenyl)-(4-nitro-phenyl)-methanone, the title compound wasobtained. LCMS (PS-A) R_(t) 1.79 [M+H]⁺ 339. ¹H NMR (Me-d₃-OD) δ 8.27(2H, d), 7.98 (2H, s), 7.80 (2H, d), 7.65 (2H, d), 7.52 (2H, d), 4.00(2H, dd), 2.73 (3H, s)—CH(OH) signal presumed to be under water peak.

Example 922-(3-Chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

By following the procedure described in Example 87B and Example 42C butreplacing 1-(4-bromo-phenyl)-2-methylamino-ethanol with2-amino-1-(4-bromo-phenyl)-ethanol and chlorobenzene with2-chloroanisole, the title compound was obtained. LCMS (PS-B3) R_(t)2.55 [M+H]⁺ 328.20. ¹H NMR (Me-d₃-OD) δ 3.65-3.70 (2H, d), 3.90 (3H, s),4.30-4.35 (1H, t), 7.05-7.10 (1H, d), 7.30-7.35 (1H, d), 7.40 (1H, s),7.45-7.50 (2H, d), 7.70-7.75 (2H, d), 8.60 (2H, s).

Example 932-(4-Chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine93A. 2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine

2-Amino-1,1-bis-(4-chloro-phenyl)-ethanol (293 mg, 1.04 mmol) wasdissolved in pyridine-HF (2 ml) with cooling. After 24 hours the mixturewas diluted into 1N sodium hydroxide solution and extracted with DCM(×3). Each extract was dried (MgSO₄) and filtered before being combinedand concentrated to give a residue which was purified by columnchromatography (SiO₂), eluting with 0.5% triethylamine in ethyl acetateto afford the title compound (192 mg, 65%); LCMS (PS-B3) R_(t) 3.34 min[M−F⁻]⁺ 266. ¹H NMR (DMSO-d₆) δ 3.41 (2H, d), 7.39-7.46 (8H, m).

93B.2-(4-Chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 except that heating was carried outat 100° C. for 5 minutes using 300 W power in a CEM microwave, to obtainthe title compound. LCMS (PS-B4) R_(t) 6.69 min [M−F⁻]⁺ 296. ¹H NMR(Me-d₃-OD) δ 4.04 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H,d).

Example 943-(3,4-Dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-propylamine

By following the procedure described in Example 60 but replacing6-chloro-nicotinonitrile with 6-chloro-pyridine-3-carbaldehyde andreplacing 3-methyl-1-trityl-1H-pyrazole-4-boronic acid with1-trityl-1H-pyrazole-4-boronic acid, and then following the proceduredescribed in Example 8, the title compound could be obtained.

Example 952-(4-Chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

By following the procedure described in Example 87, but replacing4-oxo-piperidine-1-carboxylic acid tert-butyl ester with(2-oxo-ethyl)-carbamic acid tert-butyl ester, the title compound couldbe obtained.

Example 964-(2-Chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 14, but replacingchlorobenzene with 1-chloro-2-fluorobenzene, the title compound can beobtained.

Example 971-{(3,4-Dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine97A. (4-Chloro-phenyl)-(3,4-dichloro-phenyl)-methanol

Commercially available chlorophenyl magnesium bromide and3,4-dichlorobenzaldehyde can be reacted together according to the methoddescribed in J. Medicinal Chem., (2000), 43(21), 3878-3894 to give thetitle compound.

97B. 1,2-Dichloro-4-[chloro-(4-chloro-phenyl)-methyl]-benzene

The product of Example 97A can be reacted with SO₂Cl₂ according to themethod described in Organic Letters, (2003), 5(8), 1167-1169 to give thetitle compound.

97C.1-{(3,4-Dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine

The title compound may be prepared from the compound of Example 97C byusing the method and conditions described in Zhongguo Yaowu Huaxue Zazhi(2002), 12(3), 125-129.

Example 982-(3,4-Dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

By following the procedure described in Example 42 but, in Example 42B,replacing chlorobenzene with 1,2-dichloro-benzene, the title compoundcan be obtained

Example 99{2-(3-Chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 42 but, in step 42B,substituting 2-chloroanisole for chlorobenzene, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 2.03 [M+H]⁺ 342. ¹H NMR (Me-d₃-OD) δ 2.45(3H, s), 3.22 (2H, d), 3.85 (3H, s), 4.15 (1H, t), 7.04 (1H, d), 7.33(1H, d), 7.27-7.34 (3H, m), 7.55 (2H, d), 7.92 (2H, s).

Example 1004-{4-[2-Azetidin-1-yl-1-(4-chloro-phenoxy)-ethyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 42A, but replacingmethylamine with azetidine and following the procedure in Example 45,the title compound could be obtained

Example 1013-(3-Chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 61, but replacingimidazole with potassium phthalimide in step 61A and replacingchlorobenzene with 1-chloro-2-methoxy-benzene in 61B, and then removingthe phthaloyl protecting group under the conditions set out in Examples84B and 84C, the title compound may be prepared.

Example 102{3-(3-Chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

By following the procedure described in Example 61, but substitutingimidazole with methylamine in Example 61A and substituting chlorobenzenewith 1-chloro-2-methoxy-benzene in Example 61B, the title compound maybe obtained.

Example 1031-[(3-Chloro-4-methoxy-phenyl)-(4-chloro-phenyl)-methyl]-piperazine103A. (3-Chloro-4-methoxy-phenyl)-(4-chloro-phenyl)-methanol

The title compound can be prepared using the method of Example 97A butreplacing 3,4-dichlorobenzaldehyde with 3-chloro-4-methoxybenzaldehyde.

103B. 2-Chloro-4-[chloro-(4-chloro-phenyl)-methyl]-1-methoxy-benzene

The hydroxy compound of Example 103A can be converted into the titlechloro compound by following the method of Example 97B.

103C.1-[(3-Chloro-4-methoxy-phenyl)-(4-chloro-phenyl)-methyl]-piperazine

The title compound can be prepared from the product of Example 103B byfollowing the method of Example 97C.

Example 104C-(4-Chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride withC,C-bis-(4-chloro-phenyl)-methylamine, the title compound could beobtained.

Example 105{2-(4-Chloro-phenyl)-2-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine105A.2-(4-Chloro-phenyl)-N-methyl-2-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-acetamide

2,2-Bis-(4-chloro-phenyl)-N-methyl-acetamide was prepared by thereaction of the commercially available corresponding carboxylic acidwith methylamine using the method of Example 21a. The N-methyl-acetamidecompound was then converted to the title compound by the methoddescribed in Example 1.

LCMS (PS-B3) R_(t) 4.21 min; m/z [M+H]⁺ 582.

105B.2-(4-Chloro-phenyl)-N-methyl-2-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-acetamide

The trityl-protected compound of example 104A was deprotected by themethod described in example 60D to give the title compound.

LCMS (PS-B3) R_(t) 2.41 min; m/z [M+H]⁺ 340. ¹H NMR (methanol-d₄) δ 2.40(3H, s), 2.78 (3H, s), 4.95 (1H, s), 7.29-7.34 (6H, m), 7.41 (2H, d),7.69 (1H, s).

105C.{2-(4-Chloro-phenyl)-2-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

Following the procedure described in example 20B gave the titlecompound.

LCMS (PS-B3) R_(t) 2.80 min; m/z [M+H]⁺ 326. ¹H NMR (methanol-d₄) δ 2.52(3H, s), 2.75 (3H, s), 3.80 (2H, d), 4.46 (1H, t), 7.41 (4H, s), 7.49(2H, d), 7.54 (2H, d), 8.24 (1H, s).

Biological Activity Example 106 Measurement of PKA Kinase InhibitoryActivity (IC₅₀)

Compounds of the invention can be tested for PK inhibitory activityusing the PKA catalytic domain from Upstate Biotechnology (#14-440) andthe 9 residue PKA specific peptide (GRTGRRNSI), also from UpstateBiotechnology (#12-257), as the substrate. A final concentration of 1 nMenzyme is used in a buffer that includes 20 mM MOPS pH 7.2, 40 μMATP/γ³³P-ATP and 5 M substrate. Compounds are added indimethylsulphoxide (DMSO) solution to a final DMSO concentration of2.5%. The reaction is allowed to proceed for 20 minutes before additionof excess orthophosphoric acid to quench activity. Unincorporatedγ³³P-ATP is then separated from phosphorylated proteins on a MilliporeMAPH filter plate. The plates are washed, scintillant is added and theplates are then subjected to counting on a Packard Topcount.

The % inhibition of the PKA activity is calculated and plotted in orderto determine the concentration of test compound required to inhibit 50%of the PKB activity (IC₅₀).

The compounds of Examples 1, 4, 43, 44, 45, 46, 47, 48, 49, 52, 54, 59,63, 66, 67, 73, 78, 79, 81, 82, 83, 84, 85, 86 and 90 have IC₅₀ valuesof less than 1 μM whereas the compounds of Examples 5, 7 and 80 haveIC₅₀ values of less than 15 μM.

Example 107 Measurement of PKB Kinase Inhibitory Activity (IC₅₀)

The inhibition of protein kinase B (PKB) activity by compounds can bedetermined determined essentially as described by Andjelkovic et al(Mol. Cell. Biol. 19, 5061-5072 (1999)) but using a fusion proteindescribed as PKB-PIF and described in full by Yang et al (NatureStructural Biology 9, 940-944 (2002)). The protein is purified andactivated with PDK1 as described by Yang et al. The peptide AKTide-2T(H-A-R-K-R-E-R-T-Y-S-F-G-H-H-A-OH) obtained from Calbiochem (#123900) isused as a substrate. A final concentration of 0.6 nM enzyme is used in abuffer that includes 20 mM MOPS pH 7.2, 30 μM ATP/γ³³P-ATP and 25 μMsubstrate. Compounds are added in DMSO solution to a final DMSOconcentration of 2.5%. The reaction is allowed to proceed for 20 minutesbefore addition of excess orthophosphoric acid to quench activity. Thereaction mixture is transferred to a phosphocellulose filter plate wherethe peptide binds and the unused ATP is washed away. After washing,scintillant is added and the incorporated activity measured byscintillation counting.

The % inhibition of the PKB activity is calculated and plotted in orderto determine the concentration of test compound required to inhibit 50%of the PKB activity (IC₅₀).

Following the protocol described above, the IC₅₀ values of the compoundsof Examples 1, 4, 8-10, 12-17, 20-23, 25-31, 33-35, 43, 44, 46, 47,49-52, 54, 56, 57, 59, 61, 63, 65, 66, 69, 71-73, 76-79, 81-87, 90, 91,94 and 104 have been found to be less than 1 μM whilst the compounds ofExamples 2, 3, 5, 6, 7, 11, 18, 19, 24, 32, 36, 45, 48, 53, 55, 58, 60,64, 67, 68, 75, 80 and 89 each have IC₅₀ values of less than 5 μM, andthe compounds of Examples 40, 41, 62 and 70 each have IC₅₀ values ofless than 50 μM.

Pharmaceutical Formulations Example 108 (i) Tablet Formulation

A tablet composition containing a compound of the formula (I) isprepared by mixing 50 mg of the compound with 197 mg of lactose (BP) asdiluent, and 3 mg magnesium stearate as a lubricant and compressing toform a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of theformula (I) with 100 mg lactose and filling the resulting mixture intostandard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for administration by injection can be preparedby dissolving a compound of the formula (I) (e.g. in a salt form) inwater containing 10% propylene glycol to give a concentration of activecompound of 1.5% by weight. The solution is then sterilised byfiltration, filled into an ampoule and sealed.

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving inwater a compound of the formula (I) (e.g. in salt form) (2 mg/ml) andmannitol (50 mg/ml), sterile filtering the solution and filling intosealable 1 ml vials or ampoules.

(iv) Subcutaneous Injection Formulation

A composition for sub-cutaneous administration is prepared by mixing acompound of the formula (I) with pharmaceutical grade corn oil to give aconcentration of 5 mg/ml. The composition is sterilised and filled intoa suitable container.

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

The invention claimed is:
 1. A method of inhibiting protein kinase A(PKA) or protein kinase B (PKB), the method comprising contacting thePKA or PKB with a compound having the formula (IV):

or a salt, solvate, or tautomer thereof, wherein z is 0, 1 or 2; R¹ isunsubstituted phenyl or phenyl substituted with 1, 2, 3 or 4substituents independently selected from hydroxy, C₁₋₄ acyloxy,fluorine, chlorine, bromine, trifluoromethyl, cyano, C₁₋₄ hydrocarbyloxyand C₁₋₄ hydrocarbyl optionally substituted by C₁₋₂ alkoxy or hydroxy;R² and R³ are independently selected from hydrogen and methyl; R⁴ isselected from hydrogen and methyl; R⁵ is selected from hydrogen andmethyl; and R²⁰ is selected from hydrogen, methyl, hydroxy and fluorine,provided that when z is 0, R²⁰ is other than hydroxy.
 2. A combinationcomprising: a compound having the formula (IV):

or a salt, solvate, or tautomer thereof, wherein z is 0, 1 or 2; R¹ isunsubstituted phenyl or phenyl substituted with 1, 2, 3 or 4substituents independently selected from hydroxy, C₁₋₄ acyloxy,fluorine, chlorine, bromine, trifluoromethyl, cyano, C₁₋₄ hydrocarbyloxyand C₁₋₄ hydrocarbyl optionally substituted by C₁₋₂ alkoxy or hydroxy;R² and R³ are independently selected from hydrogen and methyl; R⁴ isselected from hydrogen and methyl; R⁵ is selected from hydrogen andmethyl; and R²⁰ is selected from hydrogen, methyl, hydroxy and fluorine,provided that when z is 0, R²⁰ is other than hydroxy, and one or moreother therapeutic agents.
 3. A combination according to claim 2 whereinat least one of the one or more other therapeutic agents is selectedfrom: Topoisomerase I inhibitors; Antimetabolites; Tubulin targetingagents; DNA binder and topoisomerase II inhibitors; Alkylating Agents;Monoclonal Antibodies; Anti-Hormones; Signal Transduction Inhibitors;Proteasome Inhibitors; DNA methyl transferases; and Cytokines andretinoids.
 4. A combination according to claim 2 wherein the group R¹has one or two substituents selected from fluorine, chlorine,trifluoromethyl, methyl and methoxy.
 5. A combination according to claim4 wherein R¹ is a mono-chlorophenyl or dichlorophenyl group.
 6. Acombination according to claim 2 wherein R² and R³ are both hydrogen. 7.A combination according to claim 2 comprising a compound which is:2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine;2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;{3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;{3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;{3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(R);{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(S); dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R);2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S);{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;{2-(4-methoxy-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;{3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;{2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;{2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol;3-(4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;{2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;or C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine; or asalt, solvate, or tautomer thereof.
 8. A combination according to claim2 wherein the compound is in the form of a salt.
 9. A combinationaccording to claim 2 wherein the compound is2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol or asalt or tautomer thereof.
 10. A combination according to claim 9 whereinthe compound is a salt of2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol. 11.A combination according to claim 10 wherein the compound is in the formof a hydrochloride salt.
 12. A combination according to claim 11 whereinthe compound is in the form of a dihydrochloride salt.
 13. A combinationaccording to claim 2 wherein the compound having the formula (IV), orthe salt, solvate, or tautomer thereof, and the one or more othertherapeutic agents are formulated together in a dosage form.
 14. Acombination according to claim 13 wherein the compound is2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol or asalt or tautomer thereof.
 15. A combination according to claim 14wherein the compound is in the form of a hydrochloride salt.
 16. Acombination according to claim 15 wherein the compound is in the form ofa dihydrochloride salt.
 17. A combination according to claim 2 whereinthe compound having the formula (IV), or the salt, solvate, or tautomerthereof, and the one or more other therapeutic agents are formulatedseparately and presented together in the form of a kit.
 18. Acombination according to claim 17 wherein the compound is2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol or asalt or tautomer thereof.
 19. A combination according to claim 18wherein the compound is in the form of a hydrochloride salt.
 20. Acombination according to claim 19 wherein the compound is in the form ofa dihydrochloride salt.